Treatment Of Cancer Research Articles

Holistic approaches to mitigating psychological distress in gynecological cancer patients

This article delves into the psychological impact of gynecological malignancies and suggests pathways to improve the quality of life (QoL) for affected patients. Building on Shang et al 's comprehensive analysis, this piece integrates insights from various studies to highlight the profound influence of psychological and physical symptoms on patients undergoing treatment for gynecological cancers. The study underscores that anxiety and depression significantly exacerbate the disease's toll. Factors such as physical exercise and digital and interactive health interventions show promise in mitigating these adverse effects. The article emphasizes the necessity for a holistic care approach that addresses both physical and emotional needs. Recommendations include enhanced training for healthcare providers, public awareness campaigns, streamlined diagnostic pathways, and improved access to specialist care. These integrated strategies aim to ensure that women facing gynecological cancers can maintain an optimal QoL through comprehensive and multidisciplinary care models.

Experimental and computational studies on possibility of using glucose diazacrown cryptand as a carrier for anticancer drugs busulfan and lomustine

AbstractDrug carriers play a very important role in pharmacy, especially in cancer therapy. Most drugs used in the treatment of cancer are characterized by poor solubility in water and lack of selectivity in their toxic effects on normal and cancer cells. Administration of the drug in the form of a complex with an appropriately selected carrier can significantly improve its therapeutic effect and reduce side effects. In this study, the possibility of using the cryptand L1, containing two diazacrown ethers and two saccharide groups, as a potential drug carrier is investigated. In order to determine whether it can form complexes with drugs, the cryptand L1 and its complexes with two anticancer drugs, busulfan (BSF) and lomustine (CCNU), were synthesized. Their selected structural and energetic properties were investigated using both experimental and computational methods. Additionally, water solubility and cytotoxicity tests were performed for all compounds. The measured 1H NMR spectra confirm that L1 forms complexes L1:BSF and L1:CCNU, the solubility of which in water appears to be much higher than that of the pure drugs. The results of DFT calculations made in water described with the implicit solvent model confirm high stability of L1:BSF and L1:CCNU and indicate that L1 forms with the drugs mainly non-inclusion complexes. However, additional tests with 20 H2O molecules explicitly included in the model suggest that both inclusion and non-inclusion forms can occur in a real solution. Cytotoxicity studies show that the macrocycle L1 is non-toxic towards both normal and cancer cells, and its complexes with drugs show greater selectivity towards cancer cells. Interestingly, while the cytotoxicity of the L1:BSF complex is stronger than that of pure BSF, the relationship is opposite in the case of L1:CCNU and CCNU. Therefore, L1 can be considered as a potential drug carrier, especially for those drugs that have weak activity on cancer cells.

Lived experiences of lymphoma patients with sexual dysfunction and related sexual distress during cancer treatment

Lived experiences of lymphoma patients with sexual dysfunction and related sexual distress during cancer treatment

Application of Intelligent Management Model Based on Electronic Patient-Reported Outcome During Immunotherapy in Patients with Gastric Cancer: A Single-Center Retrospective Study

Aims/Background Gastric cancer is the third leading cause of cancer-related death worldwide, which seriously affects the health of patients. Immunotherapy is a commonly used clinical treatment for gastric cancer, but the adverse events caused by it seriously affect the prognosis of patients. Therefore, it is necessary to control and manage the disease risk of patients during immunotherapy. To explore the effect of applying an intelligent management model based on electronic patient-reported outcome (ePRO) in patients with gastric cancer during immunotherapy. Methods The clinical data of 184 gastric cancer patients receiving immunotherapy in The Fourth Hospital of Hebei Medical University from September 2021 to September 2023 were retrospectively analyzed. Ninety patients receiving ePRO-based intelligent management were selected, and 85 patients were included in the observation group after excluding 5 patients. For the reference group, 94 patients receiving common case management were selected, with 90 patients being included after excluding 4 patients. After 6 months of follow-up, the nutritional status score, quality of life, treatment compliance and adverse events were compared between the two groups. Results No significant difference was detected in nutritional status and World Health Organization Quality of Life-BREF (WHOQOL-BREF) scores of the patients before discharge (p > 0.05). After 2 months of follow-up, compared with the reference group, the observation group had a higher proportion of patients in grade A and grade B, which was not statistically significant (p > 0.05), and significantly higher physiological and psychological scores (p < 0.001), but showed no meaningful differences in other fields (p > 0.05). After 4 months of follow-up, the nutritional status in the observation group was significantly improved (p < 0.05), and the subjects displayed higher WHOQOL-BREF scores (p < 0.05) than those in the reference group. No significant difference in the incidence of adverse events was detected (p > 0.05). After 6 months of follow-up, the treatment compliance of the observation group was 83.53%, which was significantly higher than that of the reference group (70.00%; p < 0.05). Conclusion The intelligent management model based on ePRO is conducive to improving the nutritional status of patients with gastric cancer during immunotherapy, as well as enhancing their quality of life and treatment compliance, making it worthy of clinical application.

Early Palliative Care Following Aborted Cancer Surgery: Results of a Prospective Feasibility Trial

Background: Although resection is generally necessary for curative-intent treatment of most solid organ cancers, surgery is occasionally aborted due to intraoperative findings. Following aborted cancer surgery, patients have unique care needs that specialized palliative care (PC) providers may be best equipped to manage. We hypothesized that early ambulatory PC referral following aborted cancer surgery would be feasible and acceptable. Methods: This single-institution prospective clinical trial enrolled adult patients with gastrointestinal or hepatopancreatobiliary cancer with no prior PC exposure who had curative-intent oncologic surgery that was unexpectedly aborted. The primary endpoint was the completion of an ambulatory PC consultation within 30 days of enrollment. Secondary outcomes included changes in standardized measures of quality-of-life (QOL) and anxiety/depression during the 3-month follow-up. Results: Among 25 enrolled participants, the mean age was 65.3 ± 9.9 years, 68% were male, and 88% were White. The most common types of cancers were pancreatic (44%), hepatobiliary (20%), and colorectal (12%); reasons for aborting surgery were occult metastatic disease (52%) and local unresectability (36%). Only 13 of 25 (52%) met the primary endpoint of ambulatory PC within 30 days, less than the prespecified threshold of 70%. Overall, 16 (64%) patients completed ambulatory PC consultation a mean of 29.2 ± 15.8 days after enrollment. Of the 9 (36%) who did not, reasons included patient preference (n = 4), withdrawal from study (n = 1), lost to follow-up (n = 1), scheduling conflict (n = 1), and required inpatient PC before discharge (n = 2). Anxiety (4.94 ± 3.56 vs 3.35 ± 2.60, P = 0.06), depression (4.18 ± 4.02 vs 4.76 ± 3.44, P = 0.49), and QOL (82.44 ± 11.41 vs 82.03 ± 15.37, P = 0.92) scores did not significantly differ at 3-month follow-up compared to baseline. Conclusions: Barriers to early ambulatory palliative care consultation exist after aborted cancer surgery. Given the unique and complex care needs of this patient population, additional research is needed to optimize supportive care strategies.

The Impact of Mindfulness-Based Meditation and Yoga on Stress, Body Image, Self-esteem, and Sexual Adjustment in Breast Cancer Patients Undergoing Modified Radical Mastectomy

Background Surgical interventions are commonly utilized in the treatment of breast cancer; however, they can elicit adverse effects on women’s perceptions of femininity, leading to stress, negative body image, diminished self-esteem, and challenges in sexual adjustment. Objective This study investigates the efficacy of mindfulness-based meditation and yoga in alleviating stress, enhancing self-esteem, improving body image, and facilitating sexual adjustment among women undergoing modified radical mastectomy. Methods Using a prospective (pretest, posttest, and second-month follow-up), 2-arm (1:1), randomized controlled experimental design, the study involved 39 women (intervention group = 19, control group = 20) undergoing modified radical mastectomy. The intervention group participated in face-to-face mindfulness-based meditation and yoga sessions lasting approximately 90 minutes each over an 8-week period. Results Following the intervention, significant reductions in perceived stress and the significance attributed to breasts in sexuality were observed (P < .05), accompanied by increases in self-esteem and body perception (P < .05). However, no significant differences were observed in sexual adjustment (P > .05). Conclusions Mindfulness-based meditation and yoga interventions demonstrated efficacy in mitigating perceived stress, enhancing self-esteem, and improving body perception among women undergoing modified radical mastectomy. The findings advocate for the integration of mindfulness-based stress reduction programs, particularly during the preoperative phase, to support oncological patients, particularly those with breast cancer. Implications for Practice Psychosocial aspects such as body image, self-esteem, and sexual adjustment following radical mastectomy are frequently overlooked in clinical care. This research highlights the potential benefits of incorporating mindfulness-based yoga and meditation techniques into nursing interventions to alleviate stress and enhance body confidence among women undergoing mastectomy.

Development, Validation, and Visualization of a Web-Based Nomogram to Predict the Risk of Psychological Distress in Patients Undergoing Chemotherapy After Breast Cancer Surgery

Background Psychological distress of postoperative chemotherapy patients with breast cancer is significant and has a serious impact on their quality of survival. Risk prediction models can efficiently assess patients’ psychological distress and risk factors. Objectives To investigate the factors influencing psychological distress in postoperative chemotherapy patients with breast cancer and construct a nomogram model to predict the occurrence of psychological distress in patients. Methods Two hundred forty-seven women in treatment for breast cancer who were postoperative and receiving chemotherapy were recruited. Participants completed a distress management screening measure, a numerical rating scale, the Pittsburgh Sleep Quality Index, and demographic and clinical items. Results Experiencing significant psychological distress was reported by 65.6% of participants. The psychological distress risk prediction model included 5 variables: financial problems, appearance/shape, distant metastases, the Numerical Rating Scale Pain score, and fatigue. A web calculator was designed based on the model (https://77nomogram.shinyapps.io/dynnomapp/). Conclusions This study found that financial and appearance/shape problems, distant metastases, pain scores, and fatigue were predictors of greater psychological distress in women undergoing chemotherapy after breast cancer surgery. The model constructed in this study has good predictive efficacy. Implications for practice This web-based nomogram model can help healthcare professionals quickly assess the likelihood of psychological distress in patients and screen for risk factors for psychological distress.

Impact of multidisciplinary team discrepancies on comparative lung cancer outcome analyses and treatment equality

Impact of multidisciplinary team discrepancies on comparative lung cancer outcome analyses and treatment equality

Roles of posttranslational modifications in lipid metabolism and cancer progression

AbstractLipid metabolism reprogramming has emerged as a hallmark of malignant tumors. Lipids represent a complex group of biomolecules that not only compose the essential components of biological membranes and act as an energy source, but also function as messengers to integrate various signaling pathways. In tumor cells, de novo lipogenesis plays a crucial role in acquiring lipids to meet the demands of rapid growth. Increasing evidence has suggested that dysregulated lipid metabolism serves as a driver of cancer progression. Posttranslational modifications (PTMs), which occurs in most eukaryotic proteins throughout their lifetimes, affect the activity, abundance, function, localization, and interactions of target proteins. PTMs of crucial molecules are potential intervention sites and are emerging as promising strategies for the cancer treatment. However, there is limited information available regarding the PTMs that occur in cancer lipid metabolism and the potential treatment strategies associated with these PTMs. Herein, we summarize current knowledge of the roles and regulatory mechanisms of PTMs in lipid metabolism. Understanding the roles of PTMs in lipid metabolism in cancer could provide valuable insights into tumorigenesis and progression. Moreover, targeting PTMs in cancer lipid metabolism might represent a promising novel therapeutic strategy.

Group medical visits in cancer survivorship care: a scoping review

Abstract Background More than 60% of cancer survivors report unmet physical, psychosocial, and informational needs. The care of cancer survivors includes surveillance, health maintenance monitoring, referral for long-term adverse effects of cancer treatment, and coordination of care. Group medical visits (GMV) include medical care, education, and peer support and can be used to facilitate the delivery of multidisciplinary survivorship care. We aimed to characterize the current state of related research describing the role of GMV in cancer survivorship care. Methods For this scoping review, we searched for published literature using PubMed, Embase, and other resources. We included intervention studies of multidisciplinary care involving GMVs of adult patients with a history of cancer requiring the presence of medical personnel, physicians, advanced practitioners, or oncology nurses. We included studies that focused on broad cancer survivorship care, rather than those using specific modalities, such as yoga, or limited to specific aspects of cancer survivorship care, such as weight loss. We characterized the studies by cancer type, structure of GMVs, and reported outcomes. Results We identified 2311 studies (2122 from PubMed and 189 from Embase). We excluded 1524 duplicates and screened 787 studies for title and abstract review. Finally, 63 studies were retrieved for full-text review, and six were included in this scoping review. Of the included studies, four were non-randomized, and two were randomized. Breast cancer was the most common site (4); other studies included breast and other cancers (1) and hematopoietic transplant cancer survivors (1). There was heterogeneity in the structure and frequency of sessions and the survivorship domains addressed. The outcomes studied included quality of life, healthcare utilization, and costs. Conclusions Limited high-quality research exists on the role of GMV in cancer survivorship. Though shown to be effective in chronic disease, the evidence for the effectiveness of this important and widely used approach in multidisciplinary survivorship care remains inconsistent and preliminary; the literature to date provides a starting point for larger-scale studies of GMV in cancer survivorship care. Implications for Cancer Survivors While Group medical visits are a promising intervention to provide multidisciplinary care, larger studies are needed to support their benefit in the care of cancer survivors.

Global disparities in cancer care: Bridging the gap in affordability and access to medications between high and low‐income countries

AbstractBackgroundCancer remains a significant challenge for health care systems, despite notable progress in the field. These advancements have significant financial implications that disproportionately affect low‐income countries. This review article aims to explore the present state of drug development, assessing the availability of drugs in different income countries, and proposing potential solutions to address the inequality in access to new cancer treatments.MethodsA search was conducted on MEDLINE and PubMed on October 2, 2023 and updated on December 14, 2023, limited to English language articles.ResultsThere is a projected rise in cancer cases worldwide, particularly in low‐income countries where most cancer‐related deaths are expected. Although the approval rate of cancer treatments has risen, their excessive cost and lack of affordability pose significant barriers to widespread access. Disparities in the costs of crucial cancer medications are influenced by geographic location and procurement connections. Potential solutions to address the inequity in drug distribution include sharing production secrets, implementing price discrimination, international funding, improved primary health care measures, and the implementation of cost‐effective screening methods.ConclusionPreventing, screening for, and treating cancer should be a global priority with minimal differences in access to therapy among various countries.

Use of Adaptive Conjoint Analysis–Based Values Clarification in a Patient Decision Aid Is Not Associated with Better Perceived Values Clarity or Reduced Decisional Conflict but Enhances Values Congruence

Background Evidence is lacking on the most effective values clarification methods (VCMs) in patient decision aids (PtDAs). We tested the effects of an adaptive conjoint analysis (ACA)–based VCM compared with a ranking-based VCM and no VCM on several decision-related outcomes, with the decisional conflict and its subscale “perceived values clarity” as primary outcomes. Design Online experimental study with 3 conditions: no VCM versus ranking-based VCM versus ACA-based VCM ( N = 282; Mage = 63.11 y, s = 12.12), with the latter 2 conditions including attributes important for a lung cancer treatment decision. We assessed 1) decisional conflict, 2) perceived values clarity (decisional conflict subscale), 3) perceived cognitive load, 4) anticipated regret, 5) ambivalence, 6) preparedness for decision making, 7) hypothetical treatment preference, and 8) values congruence (proxy). We performed analysis of covariance and linear regression. Age and level of deliberation were included as potential moderators, and we controlled for subjective numeracy (covariate). We exploratively tested the moderating effects of subjective numeracy and health literacy (without covariates). Results We found no significant effect of type of VCM on overall decisional conflict or perceived values clarity. Age had a moderating effect: in younger participants, no VCM (v. ranking-based VCM) led to more values clarity, while in older participants, a ranking-based VCM (v. no VCM) led to more values clarity. Completing the ACA-based VCM, compared with no VCM, resulted in more values congruence. Limitations The hypothetical choice situation might have induced lower levels of cognitive/affective involvement in the decision. Conclusions This study found mixed effects of an ACA-based VCM. It did not decrease decisional conflict or increase perceived values clarity, yet it did improve values congruence. Implications Completion of an ACA-based VCM in a PtDA may increase values congruence. Highlights An adaptive conjoint analysis or a ranking-based values clarification method did not decrease analog patients’ decisional conflict nor did it increase their perceived values clarity. In younger participants, no VCM (v. ranking-based VCM) led to more values clarity, while in older participants, a ranking-based VCM (v. no VCM) led to more values clarity. An adaptive conjoint analysis task for values clarification resulted in more values congruence.

Recent advancements at ASCO 2024 in PD-L1 and PD-1 bispecific antibodies.

Recent advancements in cancer immunotherapy have spotlighted the PD-1/PD-L1 pathway, crucial for its role in immune checkpoint regulation. Traditional inhibitors, though successful, face challenges like resistance and adverse effects. Bispecific antibodies targeting PD-1 and PD-L1 present a ground-breaking solution by simultaneously engaging multiple immune regulatory molecules. Developments in PD-1/PD-L1 bispecific antibodies up to now have been summarized, and the latest findings from the 2024 ASCO conference are presented, revealing that bispecific antibodies exhibit robust efficacy in treating various types of cancers, marking a significant step forward in cancer treatment.

Abstract PR010: TRPV1+ sensory innervation as a novel driver of ovarian cancer progression

Abstract Introduction: A primary challenge currently faced in ovarian cancer (OVCA) treatment is that patient prognoses remain poor despite current therapeutic interventions. Overall survival for OVCA patients with advanced disease is <30%, and most patients recur within 5 years. As such, there is a critical need for new therapies that can overcome OVCA chemoresistance and produce meaningful increases in patient survival. Recent efforts that have targeted the tumor microenvironment (TME), such as immune checkpoint inhibitors, have been successful in some cancers but have limited therapeutic benefit when used to treat OVCA. Thus, new TME targeting therapies must be developed to effectively treat OVCA patients. A novel TME component ripe for therapeutic targeting are the nerve fibers that infiltrate tumors. Recent studies in several cancers have shown that tumor innervation can promote tumor growth/metastasis. However, in ovarian cancer the role of innervation in promoting cancer progression remains a gap in knowledge. Here we show that Transient Receptor Potential Cation Channel Subfamily V Member 1 (TRPV1)+ sensory innervation plays a significant role in driving ovarian cancer progression. Methods: We performed IHC staining to determine the extent of TRPV1+ nerve infiltration in OVCA vs normal reproductive tissue in patients. We examined the ability of OVCA cells to promote tumor innervation using a neurite outgrowth assay. We utilized both syngeneic and patient derived xenograft (PDX) mouse models of ovarian cancer metastasis, where mouse or human OVCA cells were injected intraperitoneally, to explore the functional role of TRPV1+ sensory nerves in OVCA. TRPV1+ sensory nerves were ablated genetically using TRPV1 driven expression of diphtheria toxin alpha (DTA) or chemically using resiniferatoxin. TRPV1+ sensory nerves were activated pharmacologically using capsaicin. Results: Analysis of patient samples showed that TRPV1+ sensory innervation is much higher in ovarian tumors vs benign reproductive tissue. We found that conditioned media from OVCA cells was able to promote neurite outgrowth of dissociated mouse sensory neurons. Ablation of TRPV1+ sensory nerve fibers in vivo caused reduced tumor burden and prolonged survival in our syngeneic and PDX OVCA mouse models. Stimulation of TRPV1+ sensory nerves with capsaicin accelerated OVCA growth and decreased survival in tumor bearing mice. Conclusions: Our results establish TRPV1+ sensory innervation as a novel driver of OVCA growth/metastasis and a potential therapeutic target for OVCA treatment. Significance to tumor microenvironment field: Our data add to a growing body of evidence that sensory nerves are pro-tumorigenic in multiple cancer types and could be therapeutically targeted for cancer treatment. Citation Format: Matthew Knarr, Katherine Cummins, Dusan Racordon, Hunter Reavis, Timothy Lippert, Ryan Hausler, Priyanka Rawat, Jamie Moon, Dave S.B. Hoon, Roger Greenberg, Paola Vermeer, Ronny Drapkin. TRPV1+ sensory innervation as a novel driver of ovarian cancer progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR010.

Abstract PR017: Anti-metastatic immunotherapy discovery using ex vivo lung tissue cultures and high-throughput single-cell chemical transcriptomics

Abstract Introduction: Tumors systemically remodel the immune system during metastasis. Developing anti-metastatic immunotherapies that target these tumor-immune interactions to make the metastatic niche hostile colonization would represent a paradigm shift in cancer treatment. However, traditional high-throughput screening (HTS) platforms that use simple read-outs and contrived in vitro systems are ill-suited to identify such therapies. In contrast, HTS platforms that accurately model the metastatic niche and use high-dimensional read-outs such as multiplexed single-cell RNA-sequencing (scRNA-seq) can accurately profile nuanced perturbation responses in individual immune cell types and therefore have the potential to discover anti-metastatic immunotherapies. In this study, we describe the development of an ex vivo lung tissue culture HTS platform that preserves immune gene expression signatures observed in the in vivo metastatic niche and is amenable to single-cell chemical transcriptomic analysis using MULTI- seq (McGinnis et al., Nature Methods, 2019). Inspired by our recent description of myeloid cell TLR-NFκB inflammation during breast cancer lung metastasis (McGinnis et al., Cancer Cell, 2024), we then performed the first anti-metastatic immunotherapy drug screen and identified TLR-NFκB inhibitors that effectively operate on all desired myeloid cell types in the lung metastatic niche. Methods and Results: Building upon existing techniques for culturing precision-cut lung slices (Wu et al., Journal of Experimental Medicine, 2024) and patient- derived tumor fragments (Voabil et al., Nature Medicine, 2021), we established and optimized an ex vivo lung tissue culture system that enables 48-hour culturing of lung slices isolated from 4T1 tumor-bearing mice. scRNA-seq profiling revealed successful capture of all relevant immune cell types and retention of metastasis-associated gene expression programs (e.g., myeloid TLR-NFκB inflammation and neutrophil degranulation) following culture. We then scaled our platform to address how myeloid cells in the lung metastatic niche respond to perturbations targeting every component of the canonical TLR-NFκB signaling cascade. Cell-type-specific perturbation modeling and quantification of TLR-NFκB signaling inhibition identified compounds that optimally perturb all intended myeloid cell types (e.g., tissue-resident macrophages, neutrophils, and monocytes) and represent prioritized candidates for future in vivo validation studies to assess impact on metastatic disease progression. Conclusions: In this study, we describe the development and application of a novel HTS platform that couples ex vivo lung tissue cultures with single-cell chemical transcriptomics to identify anti-metastatic immunotherapy candidates. We demonstrate how our platform can identify TLR-NFκB signaling inhibitors that optimally operate in the lung metastatic niche, paving the way for future interrogation of additional metastasis-associated immune cell signaling pathways in different disease and tissue backgrounds. Citation Format: Chris McGinnis, Winnie Yao, Ansuman Satpathy. Anti-metastatic immunotherapy discovery using ex vivo lung tissue cultures and high-throughput single-cell chemical transcriptomics [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR017.

Abstract A022: Disrupting redox homeostasis initiates anti-tumor immune responses in pancreatic cancer

Abstract Although immune therapy has made impressive progress in cancer treatment, pancreatic ductal adenocarcinoma (PDAC) remains an exception, likely due to its immunosuppressive tumor microenvironment that prevents immune responses against the tumor. Our current work aims to reactivate the suppressive immune infiltrate using radiation therapy and oxidative stress to potentiate antitumor immune responses in PDAC. Our lab previously found that PDAC cells are dependent on the antioxidant peroxiredoxin-4 (PRDX4) expression. PRDX4 prevents excessive levels of reactive oxygen species in cells and while high PRDX4 expression is associated with a more aggressive disease, it is dispensable in normal tissue. As such, disrupting redox homeostasis by inhibiting PRDX4 represents a targetable vulnerability in cancer cells. To investigate the radio-sensitizing potential of PRDX4, we knocked-down (KD) PRDX4 in human pancreatic tumor cells as well as in mouse cancer cells obtained from the spontaneous KPC model (driven by the KRas and P53 mutations), in combination with radiation. Presence and quantification of DNA damage were performed by immunofluorescence, and impaired cell survival was analyzed by clonogenic assays. Changes in immune secretion were assessed by RT-qPCR and Elisa and in vitro macrophage phenotyping was performed upon exposure to tumor cell conditioned media. Our data so far show an accumulation of cytosolic DNA upon PRDX4 KD in PDAC cells, with the presence of micronuclei as well as less aggregated DNA. Interestingly, targeting PRDX4 before radiation amplifies the release of radiation-induced cytosolic DNA while significantly decreasing cell growth and survival, compared to radiation alone. Cytosolic DNA has been shown to trigger innate immune signaling in tumor cells. Consistently, PRDX4 loss induces the upregulation of many pro-inflammatory genes, including CCL5, CCL20, and CXCL10, in a STING-dependent manner. Combining PRDX4 KD with radiation leads to a higher gene upregulation of these immune stimulatory chemokines, as well as an increased protein secretion within tumor cell media. These findings support an amplified immunomodulatory effect of radiation when combined with PRDX4 loss in PDAC cells. To assess whether targeting PRDX4 can remodel the tumor microenvironment, we applied tumor conditioned media from cancer cells on isolated naive mouse CD45+/CD11c+/F4/80+ macrophages. Media from cells treated with PRDX4 KD + radiation strongly increased the migration ability of macrophages while modulating the expression of a subset of chemokine-encoding genes in immune cells. Using the spontaneous KPC model depleted for PRDX4, along with syngeneic orthotopic models, we are now aiming to confirm this radio-sensitizing and immune-modulatory potential of PRDX4 in vivo. The aggressiveness of PDAC requires research towards novel treatment strategies and our data strongly support evidence for targeting cancer metabolism, particularly antioxidant systems, in synergy with existing cancer therapies, like radiation and immune therapy. Citation Format: Lucie Malbeteau, Emily Poulton, Vishal Pandya, Marianne Koritzinsky. Disrupting redox homeostasis initiates anti-tumor immune responses in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A022.

Abstract PR013: A vagal sensory-to-sympathetic axis restrains anti-tumor immunity

Abstract Solid tumors are innervated by distinct branches of the peripheral nervous system, and increased tumor innervation has been associated with poor cancer outcomes. However, it remains unexplored whether different types of nerves function together to sense and respond to a tumor, and how neural networks shape cancer immunity. As a major interoceptive system, vagal nerves sense a large variety of body signals and are critical for maintaining physiological homeostasis of visceral organs including the lung. While distinct vagal sensory neuron (VSN) subtypes have been identified to differently regulate pulmonary functions, it is unknown whether these VSNs interact with lung tumors and how they influence cancer progression. Here, we uncover that sensory nerves act through the sympathetic circuit to restrain anti-cancer immunity. Mechanistically, our data suggest that lung tumors hijack the vagal interoceptive system to activate sympathetic efferent nerves in the tumor microenvironment (TME), which in turn drive immune suppression via β2-adrenergic signaling in alveolar macrophages. Our key findings include: By applying anterograde labeling, tissue-clearing and 3D imaging to genetically engineered mouse models, we found that lung adenocarcinoma is richly innervated by vagal sensory nerves. We also showed that neurotrophic factors produced by cancer cells directly promote vagal sensory innervation. Furthermore, scRNA-seq analysis revealed tumor-induced transcriptional reprogramming of lung-innervating VSNs. Using multiple genetic tools to selectively label and deplete different VSN subtypes, we found that Npy2r + /Trpv1 + VSNs but not P2ry1 + VSNs innervate lung tumors and control lung cancer progression by inhibiting anti- cancer immunity. At the organism level, we demonstrated that vagal NPY2R/TRPV1 neurons inhibit anti-cancer immunity via the sympathetic axis. Depletion of vagal NPY2R/TRPV1 neurons resulted in reduced sympathetic nerve activity and a decreased norepinephrine level in the lung TME, whereas pharmacological activation of the sympathetic pathway suppressed the anti-tumor immune responses and restored tumor growth in mice lacking Npy2r + /Trpv1 + VSNs. At the molecular and cellular level, we identified that the vagal-to-sympathetic axis predominantly functions through β2-adrenergic signaling in alveolar macrophages (AMs) to drive immune suppression. AM depletion or selective deletion of β2-adrenergic receptor (ADRB2) in AMs derepressed the anti-tumor immunity and abolished the tumor-inhibiting effect of Npy2r + /Trpv1 + VSN ablation. Taken together, our study establishes an essential role of the sensory-to-sympathetic circuit in controlling cancer immunosurveillance, supporting the notion that the functional integration of sensory and sympathetic nerves systemically regulates anti- cancer immunity. Translationally, our findings from the preclinical model suggest that targeted disruption of the vagal sensory-to-sympathetic axis may provide new treatments for visceral organ cancers by enhancing anti-tumor immunity. Citation Format: Haohan Wei, Chuyue Yu, Bo Hu, Xing Zeng, Hiroshi Ichise, Ronald N. Germain, Rui Chang, Chengcheng Jin. A vagal sensory-to-sympathetic axis restrains anti-tumor immunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR013.

Abstract B035: Reciprocal macrophage - T cell interactions regulate anti-tumor immunity

Abstract Cancer immunotherapy (including immune checkpoint blockade (ICB)) has shown great promise in the treatment of some solid cancers, but responses in breast cancer patients are limited. While breast cancer is generally considered poorly immunogenic, the abundance of CD8+ T cells correlates with clinical response. CD8+ T cells are critical mediators of anti-tumor immunity and the main target for ICB. However, the onset of terminal functional T cell exhaustion poses a major challenge. Although T cell exhaustion has been linked to persistent antigen exposure, it remains unclear how the immune composition of the breast tumor microenvironment (TME) contributes to this dysfunctional T cell state. Breast cancers are heavily infiltrated with tumor-associated macrophages (TAMs) and their abundance correlates with T cell exhaustion and poor prognosis. Previously, we discovered a spatiotemporal co-dependency between exhausted T cells (TEX) and TAMs in mouse models of melanoma and breast cancer. We showed that TEX actively recruit monocytes to the TME and shape their differentiation trajectory into TAMs. Reciprocally, these TAMs ‘capture’ T cells in long-lived synaptic interactions that contribute to functional T cell exhaustion. Our current work is focused on studying the TEX-derived chemokines that regulate these TAM – T cell interactions in the breast TME with the ultimate goal to alleviate immune evasion and improve responsiveness of breast cancer to immunotherapy. Citation Format: Meenakshi Sudhakaran, Sofia Lombardi, Sophie Ayma, Matthew F. Krummel, Kelly Kersten. Reciprocal macrophage - T cell interactions regulate anti-tumor immunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B035.

Abstract A040: A novel stroma-mediated positive interaction between resistant and sensitive cells in non-small cell lung cancer facilitates drug resistance

Abstract Resistance to targeted therapies, particularly those inhibiting oncogenic tyrosine kinases (TKIs), presents a significant challenge in the treatment of advanced non-small cell lung cancer (NSCLC). Despite initial robust clinical responses, tumors often relapse due to the emergence of resistant cell populations. The origins of this resistance—whether it is pre-existing in a subset of tumor cells or arises de novo during treatment—remains a critical question in understanding and combating therapeutic failure. To investigate this, we developed in silico mathematical models that integrate both pre-existing and de novo resistance mechanisms within a framework that explicitly integrates the stromal niche. Our study focused on the evolutionary dynamics of NSCLC in response to therapy, using a hybrid agent-based spatial modeling framework (HAL) to simulate tumor behavior under treatment. These models were designed to simulate the complex interactions between resistant and sensitive tumor cells, mediated by the stroma, and to predict the timing of relapse based on these interactions. Our findings suggest that stroma-mediated interactions play a crucial role in the evolutionary dynamics of therapy responses, influencing the fitness and survival of both resistant and sensitive cells. Specifically, our models predict that pre-existing resistance is unlikely to be compatible with the long remission periods observed in a substantial subset of patients treated with advanced anaplastic lymphoma kinase (ALK) inhibitors. This conclusion was supported by the observed relapse times and volumetric tumor growth data from subsequent animal models. Moreover, our analyses highlight the importance of ecological factors within the tumor microenvironment in shaping the response to therapy. The spatial models we developed reveal that the stroma can foster positive interactions between resistant and sensitive cells, thereby accelerating the emergence of resistance. These insights underscore the need to consider the stromal niche when developing new therapeutic strategies and when interpreting the dynamics of drug resistance. In conclusion, our study provides new insights into the role of stroma in mediating resistance to TKIs in NSCLC. By combining mathematical modeling with experimental data, we have elucidated how stroma-mediated interactions between tumor cells can influence the evolution of resistance, challenging the assumption that pre-existing resistance alone drives relapses in TKI-treated patients. Our findings emphasize the need for adaptive therapeutic approaches that anticipate and disrupt these microenvironmental interactions to improve patient outcomes. Citation Format: Rishi M. Shah, Sagnik Yarlagadda, Mark Robertson-Tessi, Bina Desai, Tatiana Miti, Daria Miroshnychenko, David Basanta, Andriy Marusyk, Alexander Anderson. A novel stroma-mediated positive interaction between resistant and sensitive cells in non-small cell lung cancer facilitates drug resistance [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A040.

Intra- and early postoperative complications of laparoscopic and robot-assisted radical prostatectomy

Radical prostatectomy is the gold standard for the treatment of localized prostate cancer. In the last decade, new surgical technologies have been actively implemented that certainly increases the efficiency of oncourological treatment. The rate of intra- and postoperative complications of radical prostatectomy yet remains quite high. In this regard, crucial tasks of modern urology are minimizing of their number and effective treatment. In the review article, intra- and early postoperative complications of laparoscopic and robot-assisted radical prostatectomy have been considered.