Checkpoint Inhibitors In Cancer Research Articles

The C1q and gC1qR axis as a novel checkpoint inhibitor in cancer.

Understanding at the molecular level of the cell biology of tumors has led to significant treatment advances in the past. Despite such advances however, development of therapy resistance and tumor recurrence are still unresolved major challenges. This therefore underscores the need to identify novel tumor targets and develop corresponding therapies to supplement existing biologic and cytotoxic approaches so that a deeper and more sustained treatment responses could be achieved. The complement system is emerging as a potential novel target for cancer therapy. Data accumulated to date show that complement proteins, and in particular C1q and its receptors cC1qR/CR and gC1qR/p33/HABP1, are overexpressed in most cancer cells and together are involved not only in shaping the inflammatory tumor microenvironment, but also in the regulation of angiogenesis, metastasis, and cell proliferation. In addition to the soluble form of C1q that is found in plasma, the C1q molecule is also found anchored on the cell membrane of monocytes, macrophages, dendritic cells, and cancer cells, via a 22aa long leader peptide found only in the A-chain. This orientation leaves its 6 globular heads exposed outwardly and thus available for high affinity binding to a wide range of molecular ligands that enhance tumor cell survival, migration, and proliferation. Similarly, the gC1qR molecule is not only overexpressed in most cancer types but is also released into the microenvironment where it has been shown to be associated with cancer cell proliferation and metastasis by activation of the complement and kinin systems. Co-culture of either T cells or cancer cells with purified C1q or anti-gC1qR has been shown to induce an anti-proliferative response. It is therefore postulated that in the tumor microenvironment, the interaction between C1q expressing cancer cells and gC1qR bearing cytotoxic T cells results in T cell suppression in a manner akin to the PD-L1 and PD-1 interaction.

Immune checkpoint inhibitors in cancer: the increased risk of atherosclerotic cardiovascular disease events and progression of coronary artery calcium

BackgroundImmune checkpoint inhibitors (ICIs) have contributed to a significant advancement in the treatment of cancer, leading to improved clinical outcomes in many individuals with advanced disease. Both preclinical and clinical investigations have shown that ICIs are associated with atherosclerosis and other cardiovascular events; however, the exact mechanism underlying this relationship has not been clarified.MethodsPatients diagnosed with stages III or IV non-small cell lung cancer (NSCLC) at the Wuhan Union Hospital from March 1, 2020, to April 30, 2022, were included in this retrospective study. Coronary artery calcium (CAC) volume and score were assessed in a subset of patients during non-ECG-gated chest CT scans at baseline and 3, 6, and 12 months after treatment. Propensity score matching (PSM) was performed in a 1:1 ratio to balance the baseline characteristics between the two groups.ResultsOverall, 1458 patients (487 with ICI therapy and 971 without ICI therapy) were enrolled in this cardiovascular cohort study. After PSM, 446 patients were included in each group. During the entire period of follow-up (median follow-up 23.1 months), 24 atherosclerotic cardiovascular disease (ASCVD) events (4.9%) occurred in the ICI group, and 14 ASCVD events (1.4%) in the non-ICI group, before PSM; 24 ASCVD events (5.4%) occurred in the ICI group and 5 ASCVD events (1.1%) in the non-ICI group after PSM. The CAC imaging study group comprised 113 patients with ICI therapy and 133 patients without ICI therapy. After PSM, each group consisted of 75 patients. In the ICI group, the CAC volume/score increased from 93.4 mm3/96.9 (baseline) to 125.1 mm3/132.8 (at 12 months). In the non-ICI group, the CAC volume/score was increased from 70.1 mm3/68.8 (baseline) to 84.4 mm3/87.9 (at 12 months). After PSM, the CAC volume/score was increased from 85.1 mm3/76.4 (baseline) to 111.8 mm3/121.1 (12 months) in the ICI group and was increased from 74.9 mm3/76.8 (baseline) to 109.3 mm3/98.7 (12 months) in the non-ICI group. Both cardiovascular events and CAC progression were increased after the initiation of ICIs.ConclusionsTreatment with ICIs was associated with a higher rate of ASCVD events and a noticeable increase in CAC progression.

Blood neutrophil subset predicts the success of immune checkpoint inhibitors in cancer.

Blood neutrophil subset predicts the success of immune checkpoint inhibitors in cancer.

Hepatobiliary complications of immune checkpoint inhibitors in cancer.

Immune checkpoint inhibitors (ICIs) have dramatically changed the landscape of cancer therapy. Over the last decade, both their primary focus in trials and clinical application have exponentially risen, with repeated demonstrations of their efficacy in improving survival in various cancer types. The adverse effects of these drugs on various organ systems were recognised in early phase studies. Given their relatively new emergence on the market, there has been increasing interest into short- and long-term effects and management of ICIs in real-world settings. ICI-related hepatobiliary toxicities are often challenging to diagnose and difficult to distinguish from other causes of deranged liver biochemical tests. The aim of this review is to provide an up-to-date and detailed exploration of the hepatobiliary complications of ICIs, including pathogenesis and approaches to diagnosis and management.

Targeting alternative splicing as a new cancer immunotherapy-phosphorylation of serine arginine-rich splicing factor (SRSF1) by SR protein kinase 1 (SRPK1) regulates alternative splicing of PD1 to generate a soluble antagonistic isoform that prevents T cell exhaustion

BackgroundRegulation of alternative splicing is a new therapeutic approach in cancer. The programmed cell death receptor 1 (PD-1) is an immunoinhibitory receptor expressed on immune cells that binds to its ligands, PD-L1 and PD-L2 expressed by cancer cells forming a dominant immune checkpoint pathway in the tumour microenvironment. Targeting this pathway using blocking antibodies (nivolumab and pembrolizumab) is the mainstay of anti-cancer immunotherapies, restoring the function of exhausted T cells. PD-1 is alternatively spliced to form isoforms that are either transmembrane signalling receptors (flPD1) that mediate T cell death by binding to the ligand, PD-L1 or an alternatively spliced, soluble, variant that lacks the transmembrane domain.MethodsWe used PCR and western blotting on primary peripheral blood mononuclear cells (PBMCs) and Jurkat T cells, IL-2 ELISA, flow cytometry, co-culture of melanoma and cholangiocarcinoma cells, and bioinformatics analysis and molecular cloning to examine the mechanism of splicing of PD1 and its consequence.ResultsThe soluble form of PD-1, generated by skipping exon 3 (∆Ex3PD1), was endogenously expressed in PBMCs and T cells and prevents cancer cell-mediated T cell repression. Multiple binding sites of SRSF1 are adjacent to PD-1 exon 3 splicing sites. Overexpression of phosphomimic SRSF1 resulted in preferential expression of flPD1. Inhibition of SRSF1 phosphorylation both by SRPK1 shRNA knockdown and by a selective inhibitor, SPHINX31, resulted in a switch in splicing to ∆Ex3PD1. Cholangiocarcinoma cell-mediated repression of T cell IL-2 expression was reversed by SPHINX31 (equivalent to pembrolizumab).ConclusionsThese results indicate that switching of the splicing decision from flPD1 to ∆Ex3PD1 by targeting SRPK1 could represent a potential novel mechanism of immune checkpoint inhibition in cancer.

FcγRIIB expressed on CD8+ T cells limits responsiveness to PD-1 checkpoint inhibition in cancer.

Checkpoint inhibition using Fc-containing monoclonal antibodies has emerged as a powerful therapeutic approach to augment antitumor immunity. We recently showed that FcγRIIB, the only inhibitory IgG-Fc receptor, is expressed on a population of highly differentiated effector CD8+ T cells in the tumors of mice and humans, raising the possibility that CD8+ T cell responses may be directly modulated by checkpoint inhibitor binding to T cell-expressed FcγRIIB. Here, we show that despite exhibiting strong proliferative and cytokine responses at baseline, human FcγRIIBpos CD8+ T cells exhibited reduced responsiveness to both PD-1 and CTLA-4 checkpoint inhibition as compared with FcγRIIBneg CD8+ T cells in vitro. Moreover, frequencies of FcγRIIBpos CD8+ T cells were reduced after treatment of patients with melanoma with nivolumab in vivo. This reduced responsiveness was FcγRIIB dependent, because conditional genetic deletion of FcγRIIB on tumor-specific CD8+ T cells improved response to checkpoint blockade in B16 and LLC mouse models of cancer. The limited responsiveness of FcγRIIBpos CD8+ T cells was also dependent on an intact Fc region of the checkpoint inhibitor, in that treatment with Fc-devoid anti-PD-1 F(ab) fragments resulted in increased proliferation of FcγRIIBpos CD8+ T cells, without altering the response of FcγRIIBneg CD8+ T cells. Last, the addition of FcγRIIB blockade improved efficacy of PD-1 checkpoint inhibition in mouse models of melanoma, lung, and colon cancer. These results illuminate an FcγRIIB-mediated, cell-autonomous mechanism of CD8+ T cell suppression, which limits the efficacy of checkpoint inhibitors during antitumor immune responses in vivo.

Real-world pan-cancer landscape of frameshift mutations and their role in predicting responses to immune checkpoint inhibitors in cancers with low tumor mutational burden

BackgroundPembrolizumab is FDA approved for tumors with tumor mutational burden (TMB) of ≥10 mutations/megabase (mut/Mb). However, the response to immune checkpoint inhibitors (ICI) varies significantly among cancer histologies. We describe...

Cancer and sepsis.

Sepsis is one of the leading causes of death worldwide. While mortality is high regardless of inciting infection or comorbidities, mortality in patients with cancer and sepsis is significantly higher than mortality in patients with sepsis without cancer. Cancer patients are also significantly more likely to develop sepsis than the general population. The mechanisms underlying increased mortality in cancer and sepsis patients are multifactorial. Cancer treatment alters the host immune response and can increase susceptibility to infection. Preclinical data also suggests that cancer, in and of itself, increases mortality from sepsis with dysregulation of the adaptive immune system playing a key role. Further, preclinical data demonstrate that sepsis can alter subsequent tumor growth while tumoral immunity impacts survival from sepsis. Checkpoint inhibition is a well-accepted treatment for many types of cancer, and there is increasing evidence suggesting this may be a useful strategy in sepsis as well. However, preclinical studies of checkpoint inhibition in cancer and sepsis demonstrate results that could not have been predicted by examining either variable in isolation. As sepsis management transitions from a 'one size fits all' model to a more individualized approach, understanding the mechanistic impact of cancer on outcomes from sepsis represents an important strategy towards delivering on the promise of precision medicine in the intensive care unit.

Clinical impact of anti-inflammatory microglia and macrophage phenotypes at glioblastoma margins.

Glioblastoma is a devastating brain cancer for which effective treatments are required. Tumour-associated microglia and macrophages promote glioblastoma growth in an immune-suppressed microenvironment. Most recurrences occur at the invasive margin of the surrounding brain, yet the relationships between microglia/macrophage phenotypes, T cells and programmed death-ligand 1 (an immune checkpoint) across human glioblastoma regions are understudied. In this study, we performed a quantitative immunohistochemical analysis of 15 markers of microglia/macrophage phenotypes (including anti-inflammatory markers triggering receptor expressed on myeloid cells 2 and CD163, and the low-affinity-activating receptor CD32a), T cells, natural killer cells and programmed death-ligand 1, in 59 human IDH1-wild-type glioblastoma multi-regional samples (n = 177; 1 sample at tumour core, 2 samples at the margins: the infiltrating zone and leading edge). Assessment was made for the prognostic value of markers; the results were validated in an independent cohort. Microglia/macrophage motility and activation (Iba1, CD68), programmed death-ligand 1 and CD4+ T cells were reduced, and homeostatic microglia (P2RY12) were increased in the invasive margins compared with the tumour core. There were significant positive correlations between microglia/macrophage markers CD68 (phagocytic)/triggering receptor expressed on myeloid cells 2 (anti-inflammatory) and CD8+ T cells in the invasive margins but not in the tumour core (P < 0.01). Programmed death-ligand 1 expression was associated with microglia/macrophage markers (including anti-inflammatory) CD68, CD163, CD32a and triggering receptor expressed on myeloid cells 2, only in the leading edge of glioblastomas (P < 0.01). Similarly, there was a positive correlation between programmed death-ligand 1 expression and CD8+ T-cell infiltration in the leading edge (P < 0.001). There was no relationship between CD64 (a receptor for autoreactive T-cell responses) and CD8+/CD4+ T cells, or between the microglia/macrophage antigen presentation marker HLA-DR and microglial motility (Iba1) in the tumour margins. Natural killer cell infiltration (CD335+) correlated with CD8+ T cells and with CD68/CD163/triggering receptor expressed on myeloid cells 2 anti-inflammatory microglia/macrophages at the leading edge. In an independent large glioblastoma cohort with transcriptomic data, positive correlations between anti-inflammatory microglia/macrophage markers (triggering receptor expressed on myeloid cells 2, CD163 and CD32a) and CD4+/CD8+/programmed death-ligand 1 RNA expression were validated (P < 0.001). Finally, multivariate analysis showed that high triggering receptor expressed on myeloid cells 2, programmed death-ligand 1 and CD32a expression at the leading edge were significantly associated with poorer overall patient survival (hazard ratio = 2.05, 3.42 and 2.11, respectively), independent of clinical variables. In conclusion, anti-inflammatory microglia/macrophages, CD8+ T cells and programmed death-ligand 1 are correlated in the invasive margins of glioblastoma, consistent with immune-suppressive interactions. High triggering receptor expressed on myeloid cells 2, programmed death-ligand 1 and CD32a expression at the human glioblastoma leading edge are predictors of poorer overall survival. Given substantial interest in targeting microglia/macrophages, together with immune checkpoint inhibitors in cancer, these data have major clinical implications.

Human CD4 cytotoxic T lymphocytes mediate potent tumor control in humanized immune system mice

Efficacy of immune checkpoint inhibitors in cancers can be limited by CD8 T cell dysfunction or HLA-I down-regulation. Tumor control mechanisms independent of CD8/HLA-I axis would overcome these limitations. Here, we report potent CD4 T cell-mediated tumor regression and memory responses in humanized immune system (HIS) mice implanted with HT-29 colorectal tumors. The regressing tumors showed increased CD4 cytotoxic T lymphocyte (CTL) infiltration and enhanced tumor HLA-II expression compared to progressing tumors. The intratumoral CD4 T cell subset associated with tumor regression expressed multiple cytotoxic markers and exhibited clonal expansion. Notably, tumor control was abrogated by depletion of CD4 but not CD8 T cells. CD4 T cells derived from tumor-regressing mice exhibited HLA-II-dependent and tumor-specific killing ex vivo. Taken together, our study demonstrates a critical role of human CD4 CTLs in mediating tumor clearance independent of CD8 T cells and provides a platform to study human anti-tumor immunity in vivo.

Cardiovascular, Renal and Pulmonary Toxicity of Immune Checkpoint Inhibitors in Cancer: What the GP Should Know.

Immunotherapy with immune checkpoint inhibitors (ICI) is administered in different cancer types and can lead to a wide range of immune-related adverse events including toxicity in vital organs such as the lungs, the kidneys, and the heart. The main hypothesis suggests an overactivation of the immune cells in the different organs. Whereas immune-related cardiotoxicity is very rare but life threatening, ICI-induced acute kidney injury and pneumonitis are more frequent but in general less severe. Renal toxicity corresponds in more than 90% to an acute tubulo-interstitial nephritis. Checkpoint inhibitors pneumonitis is diagnosed mainly on respiratory symptoms with new radiological features, especially under the form of a cryptogenic organising pneumonia. Cardiotoxicity is predominantly marked by myocarditis but also pericarditis and arrhythmias, among others. Early recognition, temporary or definitive cessation of ICI therapy and rapid initiation of high-dose corticosteroids are the cornerstones of the management, which must to be multidisciplinary in a specialised center.

T-cell immunoglobulin and mucin-domain containing protein (TIM) structural dynamics revealed by molecular dynamics simulations.

Mucin-domain glycoproteins are characterized by extremely dense O-glycosylation that contributes to a unique, bottle-brush secondary structure which can extend away from the cell surface or form extracellular gel-like secretions. Mucin-type O-glycans are characterized by an initiating α-N-acetylgalactosamine (α-GalNAc) that is further elaborated into several core structures containing sialylation, fucosylation and/or ABO blood group antigens. As a result, mucin domains serve as highly heterogeneous swaths of glycosylation that exert both biophysical and biochemical influence on the cellular milieu. In particular, the T-cell immunoglobulin and mucin-domain containing family of proteins (TIM-1, 3, 4) decorate immune cells and act as key checkpoint inhibitors in cancer. However, their dense O-glycosylation remains enigmatic both in glycoproteomic landscape and structural dynamics, primarily due to the challenges associated with studying intrinsically disordered mucin domains. Through the discovery and use of a novel mucinase that selectively cleaves along the mucin glycoprotein backbone, we fully characterize the glycoproteomic landscape and construct the first all-atom computational model of TIM3 and TIM4. We probe how glycosylation, both type and density, affects structural and dynamical features of these proteins. Overall, we present a powerful computational workflow to better understand the detailed molecular structure of the mucinome.

REFINE (REduced Frequency ImmuNE checkpoint inhibition in cancers): A multi-arm phase II basket trial testing reduced intensity immunotherapy across different cancers

BackgroundImmune checkpoint inhibitors (ICI) have revolutionised treating advanced cancers. ICI are administered intravenously every 2–6 weeks for up to 2 years, until cancer progression/unacceptable toxicity. Physiological efficacy is observed at lower doses than those used as standard of care (SOC). Pharmacodynamic studies indicate sustained target occupancy, despite a pharmacological half-life of 2–3 weeks. Reducing frequency of administration may be possible without compromising outcomes. The REFINE trial aims to limit individual patient exposure to ICI whilst maintaining efficacy, with potential benefits in quality of life and reduced drug treatment/attendance costs. Methods/DesignREFINE is a randomised phase II, multi-arm, multi-stage (MAMS) adaptive basket trial investigating extended interval administration of ICIs. Eligible patients are those responding to conventionally dosed ICI at 12 weeks. In stage I, patients (n = 160 per tumour-specific cohort) will be randomly allocated (1:1) to receive maintenance ICI at SOC vs extended dose interval. REFINE is currently recruiting UK patients with locally advanced or metastatic renal cell carcinoma (RCC) who have tolerated and responded to initial nivolumab/ipilimumab, randomised to receive maintenance nivolumab SOC (480 mg 4 weekly) vs extended interval (480 mg 8 weekly). Additional tumour cohorts are planned. Subject to satisfactory outcomes (progression-free survival) stage II will investigate up to 5 different treatment intervals. Secondary outcome measures include overall survival, quality-of-life, treatment-related toxicity, mean incremental pathway costs and quality-adjusted life-years per patient. REFINE is funded by the Jon Moulton Charity Trust and Medical Research Council, sponsored by University College London (UCL), and coordinated by the MRC CTU at UCL.Trial RegistrationISRCTN79455488.NCT04913025EUDRACT #: 2021–002060-47.CTA 31330/0008/001–0001;MREC approval: 21/LO/0593.REFINE Protocol version 4.0.

782TiP Reduced frequency immune checkpoint inhibition in cancers (REFINE): A multi-arm phase II trial testing reduced intensity immunotherapy in different cancers

Immune checkpoint inhibitors (ICI) have revolutionised cancer treatment, resulting in long-term durable responses. In advanced disease, ICIs are administered every 2-6 weeks i.v. until cancer progression or unacceptable toxicity, which is often several years’ treatment. Physiological efficacy of anti-PD-1 antibodies (maximal receptor occupancy) is seen at lower doses than those in routine use. Pharmacodynamic studies indicate sustained target occupancy of >70% for at least 2 months, despite half-lives of 2-3 weeks.

Randomized Versus Real-World Evidence on the Efficacy and Toxicity of Checkpoint Inhibitors in Cancer in Patients with Advanced Non-small Cell Lung Cancer or Melanoma: A Meta-analysis.

BackgroundBoth randomized controlled trials (RCTs) and real-world evidence (RWE) studies provide results regarding the efficacy and toxicity of checkpoint inhibitors in cancer patients. The results from these two sources are considered complementary but whether they are comparable remains unknown.ObjectiveThe aim of this study was to compare the efficacy and toxicity of checkpoint inhibitors between RCTs and RWE studies in patients with advanced non-small cell lung cancer (NSCLC) or melanoma.Patients and MethodsTwo electronic databases were searched to identify eligible studies, either RCTs or RWE studies, investigating the efficacy or toxicity of checkpoint inhibitors given for indications that were approved by the European Medicines Agency (EMA) at the date of the last search. A meta-analysis was performed and the pooled estimates of objective response rates (ORR), progression-free survival (PFS), overall survival (OS), and toxicity and treatment discontinuation between RCTs and RWE studies were compared.ResultsIn total, 43 RWE studies and 15 RCTs were eligible, with adequate data for pooled estimates for immunotherapy indications regarding NSCLC and melanoma. No statistically significant or clinically meaningful differences in terms of pooled PFS, OS, or rates of treatment discontinuation due to toxicity between RCTs and RWE studies were observed. In some indications, a higher rate of response rates and lower rate of toxicity in favor of RWE was observed.ConclusionIn patients with melanoma or NSCLC, the clinical value of checkpoint inhibitors is evident in both RCTs and real-world settings. Some differences in response or toxicity rates in favor of RWE mainly reflects the inherent difficulties in evaluating these outcomes in RWE studies.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11523-022-00901-1.

P-020: PD1-based chimeric-switch receptor expressing NK cells recover from immune checkpoint inhibition in cancer

P-020: PD1-based chimeric-switch receptor expressing NK cells recover from immune checkpoint inhibition in cancer

Abstract 4236: Temporal inhibition of BCAT1 alters metal homeostasis leading to reversal of terminal exhaustion of CD8 T cells, increased cytotoxicity, and increased efficacy of checkpoint inhibition in cancer

Abstract We have previously demonstrated that BCAT1, the enzyme responsible for the reversible transamination of leucine in the cytosol, is a druggable target in immune-oncology: the small molecule inhibitor ERG245 dramatically increases the efficacy of anti-PD-1 treatment in the moderately immunogenic CT26 colon cancer model. We have also shown that Bcat1 gene expression is enriched in exhausted CD4+ and CD8+ intratumoral cells in cancer patients from diverse cancers. Here, we illustrate that the adoptive cell transfer (ACT) of murine CD8+ T cells treated with ERG245 increased the median survival of CT26 tumor-bearing mice from 25 days, observed with the ACT of untreated CD8+ T cells, to 32 days. This suggested that inhibition of BCAT1 prevented the known exhaustion of adoptively transferred CD8+ T cells, induced by the tumor microenvironment of CT26 tumors. To confirm this hypothesis, we developed an in vitro model of generating terminally exhausted (PD-1+TIM-3+GZMB+CXCL13+) CD8+ T cells by subjecting the cells to consecutive cycles of αCD3/αCD28 activation in the presence of TGF-β. Addition of ERG245 in the last activation cycle decreased terminal exhaustion of the cells. Mechanistically, bulk RNAseq experiments indicated and ICP analysis confirmed that inhibition of BCAT1 interfered with metal homeostasis leading to increased concentrations of Fe in the mitochondria and decreased concentrations of Zn in the nucleus of newly activated CD8+ T cells. The immediate impact of ERG245 treatment on the cells included a general decrease in the genes of processes depending on proper metal equilibrium such as cholesterol biosynthesis and ribosome biogenesis. Withdrawal of BCAT1 restored or reversed the cell phenotype leading to epigenetically altered CD8+ T cells with decreased histone acetyltransferase and histone demethylase presence, increased cytotoxicity, and increased ribosome biogenesis. Collectively, the data suggest that temporal inhibition of BCAT1 inhibition induces profound effects on CD8+ T cells including increased cytotoxicity and suppression of terminal exhaustion, thus rendering the cells rescuable by anti-PD-1 therapy. Citation Format: Adonia E. Papathanassiu, Weixing Li, Hong A. Vu. Temporal inhibition of BCAT1 alters metal homeostasis leading to reversal of terminal exhaustion of CD8 T cells, increased cytotoxicity, and increased efficacy of checkpoint inhibition in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4236.

Association of the gut microbiome with cancer immunotherapy.

Immune checkpoint inhibitors, programmed cell death-1- and cytotoxic T-lymphocyte-associated protein 4-based immunotherapy have remarkably improved survival with durable response for patients with multiple cancer type. The accurate predictors of response and toxicity to immunotherapy are still unclear and have been focused on the gut microbiome. The gut microbiome, which refers to the microorganisms and their genes, affects the host immunity both locally and systemically. Modulation of the gut microbiota alters the immune systems and affects the efficacy of immune checkpoint inhibitor. In this review, we investigate the evidence on the role of the microbiome in cancer patients and discuss the impact of microbiome on the efficacy of immune checkpoint inhibitors in cancer.

Oncogenic RAS sensitizes cells to drug-induced replication stress via transcriptional silencing of P53.

Cancer cells often experience high basal levels of DNA replication stress (RS), for example due to hyperactivation of oncoproteins like MYC or RAS. Therefore, cancer cells are considered to be sensitive to drugs that exacerbate the level of RS or block the intra S-phase checkpoint. Consequently, RS-inducing drugs including ATR and CHK1 inhibitors are used or evaluated as anti-cancer therapies. However, drug resistance and lack of biomarkers predicting therapeutic efficacy limit efficient use. This raises the question what determines sensitivity of individual cancer cells to RS. Here, we report that oncogenic RAS does not only enhance the sensitivity to ATR/CHK1 inhibitors by directly causing RS. Instead, we observed that HRASG12V dampens the activation of the P53-dependent transcriptional response to drug-induced RS, which in turn confers sensitivity to RS. We demonstrate that inducible expression of HRASG12V sensitized cells to ATR and CHK1 inhibitors. Using RNA-sequencing of FACS-sorted cells we discovered that P53 signaling is the sole transcriptional response to RS. However, oncogenic RAS attenuates the transcription of P53 and TGF-β pathway components which consequently dampens P53 target gene expression. Accordingly, live cell imaging showed that HRASG12V exacerbates RS in S/G2-phase, which could be rescued by stabilization of P53. Thus, our results demonstrate that transcriptional control of P53 target genes is the prime determinant in the response to ATR/CHK1 inhibitors and show that hyperactivation of the MAPK pathway impedes this response. Our findings suggest that the level of oncogenic MAPK signaling could predict sensitivity to intra-S-phase checkpoint inhibition in cancers with intact P53.

Checkpoint inhibition induced pruritus during cancer therapy is associated with skin IL-31 and CCL22 expression

Immune-related cutaneous adverse events (ircAEs) represent a significant clinical problem in cancer checkpoint inhibitor (CPI) therapy, the most rapidly growing cancer treatment. Mechanisms of CPI induced ircAE immunologic endotypes and their association with polarized immune responses have not been examined.