Immune Checkpoint Inhibitor Resistance Research Articles

Immune escape of head and neck cancer mediated by the impaired MHC-I antigen presentation pathway.

Tumor immune evasion is a hallmark of Head and Neck Cancers. The advent of immune checkpoint inhibitors (ICIs) in the first-line setting has transformed the management of these tumors. Unfortunately, the response rate of Head and Neck Squamous Cell Carcinomas (HNSCC) to ICIs is below 15%, regardless of the human papillomavirus (HPV) status, which might be partially related with impaired antigen presentation machinery (APM). Mechanistically, HNSCC cells are usually defective in the expression of MHC-I associated APM, while this transcriptional pathway is critical for the activation of tumor-killing effector T-cells. To specifically illuminate the phenomenon and seek for therapeutic strategies, this review summarizes the most recently identified role of genetic and functional dysregulation of the MHC-I pathway, specifically through changes at the genetic, epigenetic, post-transcriptional, and post-translational levels, which substantially contributes to HNSCC immune escape and ICI resistance. Several treatment modalities can be potentially exploited to restore APM signaling in tumors, which improves anti-tumor immunity through the activation of interferons, vaccines or rimantadine against HPV and the inhibition of EGFR, SHP-2, PI3K and MEK. Additionally, the combinatorial use of radiotherapy or cytotoxic agents with ICIs can synergize to potentiate APM signaling. Future directions would include further dissection of MHC-I related APM signaling in HNSCC and whether reversing this inhibition in combination with ICIs would elicit a more robust immune response leading to improved response rates in HNSCC. Therapeutic approaches to restore the MHC-I antigen presentation machinery in Head and Neck Cancer. (Red color texts represent the according strategies and the outcomes).

CD34 as a potential prognostic indicator for camrelizumab response in advanced non-small-cell lung cancer: insights from digital spatial profiling.

Given that only a small subset of patients with advanced non-small-cell lung cancer (aNSCLC) benefit from immune checkpoint inhibitors (ICIs), the effectiveness of ICIs is often compromised by the complex interplay within the tumor microenvironment (TME). To identify predictive biomarkers associated with ICI resistance at a multi-omics spatial level. A total of eight aNSCLC patients who received first-line anti-programmed cell death protein-1 (PD-1) monoclonal antibody camrelizumab at Shandong Cancer Hospital and Institute between 2021 and 2022 were included in the discovery cohort. An additional validation cohort of 45 samples from camrelizumab-treated aNSCLC patients was also enrolled. NanoString GeoMx® digital spatial profiling was conducted at the transcriptomic and proteomic level within pan-cytokeratin (panCK+), CD45+, and CD68+ compartments. For validation, multiplex immunofluorescence (mIF) staining was performed. Distinct spatial expression patterns and levels of immune infiltration were observed between tumor and leukocyte compartments. Higher CD34 expression in the macrophage compartment correlated with poorer prognosis and response to camrelizumab (p < 0.05). mIF validation confirmed the association of elevated CD34 expression level with reduced progression-free survival (PFS; hazard ratio (HR) = 5.011, 95% confidence interval: 1.057-23.752, p = 0.042), outperforming traditional tumor markers in predictive accuracy. Our findings identify CD34 as a novel spatial biomarker for anti-PD-1 therapy efficacy, potentially guiding the selection of aNSCLC patients who are more likely to benefit from ICI treatment. ChiCTR2000040416.

TIM-3 transcriptomic landscape with clinical and immunomic correlates in cancer.

TIM-3, an inhibitory checkpoint receptor, may invoke anti-PD-1/anti-PD-L1 immune checkpoint inhibitor (ICI) resistance. The predictive impact of TIM-3 RNA expression in various advanced solid tumors among patients treated with ICIs is yet to be determined, and their prognostic significance also remains unexplored. We investigated TIM-3 transcriptomic expression and clinical outcomes. We examined TIM-3 RNA expression data through the OmniSeq database. TIM-3 transcriptomic patterns were calibrated against a reference population (735 tumors), adjusted to internal housekeeping genes, and calculated as percentiles. Overall, 514 patients (31 cancer types; 489 patients with advanced/metastatic disease and clinical annotation) were assessed. Ninety tumors (17.5% of 514) had high (≥75th percentile RNA rank) TIM-3 expression. Pancreatic cancer had the greatest proportion of TIM-3 high expressors (36% of 55 patients). Still, there was variability within cancer types with, for instance, 12.7% of pancreatic cancers harboring low TIM-3 (<25th percentile) levels. High TIM-3 expression independently and significantly correlated with high PD-L2 RNA expression (odds ratio (OR) 9.63, 95% confidence interval (CI) 4.91-19.4, P<0.001) and high VISTA RNA expression (OR 2.71, 95% CI 1.43-5.13, P=0.002), all in multivariate analysis. High TIM-3 RNA did not correlate with overall survival (OS) from time of metastatic disease in the 272 patients who never received ICIs, suggesting that it is not a prognostic factor. However, high TIM-3 expression predicted longer median OS (but not progression-free survival) in 217 ICI-treated patients (P=0.0033; median OS, 2.84 versus 1.21 years (high versus not-high TIM-3)), albeit not retained in multivariable analysis. In summary, TIM-3 RNA expression was variable between and within malignancies, and high levels associated with high PD-L2 and VISTA checkpoints and with pancreatic cancer. Individual tumor immunomic assessment and co-targeting co-expressed checkpoints merits exploration in prospective trials as part of a precision immunotherapy strategy.

Blood-based circulating biomarkers for prediction of immune-checkpoint inhibitors efficacy in renal cell carcinoma.

Immune checkpoint inhibitors (ICI)-based combinations have become the standard first-line treatment for advanced clear cell renal cell carcinoma (ccRCC). Despite significant improvements in survival and the achievement of sustained long-term responses, a subset of patients remains refractory to ICI, and most will eventually develop resistance. Thus, identifying predictive biomarkers for ICI efficacy and resistance is essential for optimizing therapeutic strategies. Up to now, tissue-based biomarkers have not been successful as predictive biomarkers in RCC. Circulating blood-based biomarkers offer a promising alternative. These biomarkers, including circulating immune cells, soluble factors, tumor-derived markers, and those based on metabolomics, are less invasive, offer reproducibility over time, and provide a comprehensive assessment of tumor biology and patient immune status, as well as allow dynamic monitoring during treatment. This review aims to evaluate the current evidence on the different candidate circulating biomarkers being investigated for their potential to predict ICI efficacy in RCC patients.

Strategies and perspectives for addressing immune checkpoint inhibitor resistance in the era of combination immunotherapy for advanced hepatocellular carcinoma

Strategies and perspectives for addressing immune checkpoint inhibitor resistance in the era of combination immunotherapy for advanced hepatocellular carcinoma

Cancer Immunotherapy with Lipid Nanoparticles Loaded with a Stimulator of Interferon Genes Agonist against Renal Tumor Lung Metastasis.

Metastatic renal cell carcinoma (RCC) has a poor prognosis, and the major organ of metastasis is the lung. Immunotherapy with immune checkpoint inhibitors (ICIs) is the first-line therapy, but the response rates are low. Thus, the development of a more effective immunotherapy against metastatic RCC would be highly desirable. We previously demonstrated how a stimulator of an interferon gene (STING) agonist-loaded lipid nanoparticles (STING-LNPs) significantly activates natural killer (NK) cells and induces an antitumor effect against cases of melanoma lung metastasis that have shown ICI resistance. In this study, we evaluated the potential of using STING-LNPs in the treatment of lung metastatic RCC (Renca). An intravenous injection of STING-LNPs drastically decreased the amount of Renca tumor colonies. In contrast, monotherapies using ICIs showed no antitumor effect, and even a combination of ICI and STING-LNP therapies failed to enhance the antitumor effects. The main effector cells would be NK cells, and the activation of NK cells by the STING-LNPs may avoid the increased expression of immune checkpoint molecules. These findings provide useful insights into the development of an effective immunotherapy against metastatic RCC.

Overcoming Resistance Mechanisms to Immune Checkpoint Inhibitors: Leveraging the Anti-Tumor Immune Response.

As far back as 3000 years ago, the immune system was observed to play a role in mediating tumor regression. Since then, many strategies have been developed to leverage the anti-tumor immune response. However, while many patients respond to ICIs up front some do not, and many of those that do eventually experience tumor progression. Currently, there are several predictive biomarkers of the immune checkpoint inhibitor response; however, no one test appears to be universally predictive and their application varies by disease site. There are many ways in which cancer cells develop primary or acquired resistance to immune checkpoint inhibitors. Efforts to reverse resistance include ways to combat T cell exhaustion, reprogram the tumor microenvironment, increase the availability of tumor neo-antigens, target alternative immune checkpoints, restore a normal/healthy patient gut microbiome, oncolytic viruses and tumor vaccines. The most studied and most promising methods include combining ICIs with therapies targeting alternative immune checkpoints and restoring a normal/healthy patient gut microbiome. This review will discuss T cell-mediated immunity, how this is leveraged by modern immunotherapy to treat cancer and mechanisms of immune checkpoint inhibitor resistance, while highlighting strategies to overcome primary and secondary resistance mechanisms.

High HPK1+PD-1+TIM-3+CD8+ T cells infiltration predicts poor prognosis to immunotherapy in NSCLC patients

At present the efficacy of immune checkpoint inhibitors (ICIs) remains limited. The lack of responsiveness in certain patients may be attributed to CD8+ T cell exhaustion within the tumor microenvironment (TME). Hematopoietic progenitor kinase 1 (HPK1) has been identified as a mediator of T cell dysfunction, leading to our hypothesis that HPK1 positive exhausted CD8+ T cells could serve as a predictor for ICIs' efficacy in NSCLC patients, and potentially indicate key cellular subset causing ICIs resistance. Here, we retrospectively collected tumor tissue samples from 36 NSCLC patients who underwent first-line immunotherapy. Using multiplex immunohistochemistry, we visualized various PD-1+CD8+ T cell subsets and explore biomarkers for response. The analysis endpoints included overall response rate (ORR), progression free survival (PFS), and overall survival (OS), correlating them with levels of cell infiltration or effective density. We found that the proportion of PD-1+CD8+ T cell subsets did not align with predictions for ORR, PFS, and OS. Conversely, a high infiltration of HPK1+PD-1+TIM-3+CD8+ T cells was identified as an independent risk factor for both PFS (P = 0.019) and OS (P = 0.03). These cells were found to express the highest levels of Granzyme B, and the secretion of Granzyme B in CD8+ T cell subsets was related to TCF-1. In conclusion, these data suggest that a high infiltration of HPK1+PD-1+TIM-3+CD8+ T cells correlates with poor clinical outcomes in NSCLC patients receiving immunotherapy. These cells may represent terminally exhausted T cells that fail to respond to ICIs, thereby laying the groundwork for the potential integration of HPK1 inhibitors with immunotherapy to enhance treatment strategy.

Abnormal vascular structure and function within brain metastases is linked to pembrolizumab resistance.

We recently conducted a phase 2 trial (NCT028865685) evaluating intracranial efficacy of pembrolizumab for brain metastases (BM) of diverse histologies. Our study met its primary efficacy endpoint and illustrates that pembrolizumab exerts promising activity in a select group of patients with BM. Given the importance of aberrant vasculature in mediating immunosuppression, we explored the relationship between immune checkpoint inhibitor (ICI) efficacy and vascular architecture in the hopes of identifying potential mechanisms of intracranial ICI response or resistance for BM. Using Vessel Architectural Imaging, a histologically validated quantitative metric for in vivo tumor vascular physiology, we analyzed dual-echo DSC/DCE MRI for 44 patients on trial. Tumor and peri-tumor cerebral blood volume/flow, vessel size, arterial and venous dominance, and vascular permeability were measured before and after treatment with pembrolizumab. BM that progressed on ICI were characterized by a highly aberrant vasculature dominated by large-caliber vessels. In contrast, ICI-responsive BM possessed a more structurally balanced vasculature consisting of both small and large vessels, and there was a trend toward a decrease in under-perfused tissue, suggesting a reversal of the negative effects of hypoxia. In the peri-tumor region, the development of smaller blood vessels, consistent with neo-angiogenesis, was associated with tumor growth before radiographic evidence of contrast enhancement on anatomical MRI. This study, one of the largest functional imaging studies for BM, suggests that vascular architecture is linked with ICI efficacy. Studies identifying modulators of vascular architecture, and effects on immune activity, are warranted and may inform future combination treatments.

In Vitro Three-Dimensional (3D) Models for Melanoma Immunotherapy.

Melanoma is responsible for the majority of skin cancer-related fatalities. Immune checkpoint inhibitor (ICI) treatments have revolutionized the management of the disease by significantly increasing patient survival rates. However, a considerable number of tumors treated with these drugs fail to respond or may develop resistance over time. Tumor growth and its response to therapies are critically influenced by the tumor microenvironment (TME); it directly supports cancer cell growth and influences the behavior of surrounding immune cells, which can become tumor-permissive, thereby rendering immunotherapies ineffective. Ex vivo modeling of melanomas and their response to treatment could significantly advance our understanding and predictions of therapy outcomes. Efforts have been directed toward developing reliable models that accurately mimic melanoma in its appropriate tissue environment, including tumor organoids, bioprinted tissue constructs, and microfluidic devices. However, incorporating and modeling the melanoma TME and immune component remains a significant challenge. Here, we review recent literature regarding the generation of in vitro 3D models of normal skin and melanoma and the approaches used to incorporate the immune compartment in such models. We discuss how these constructs could be combined and used to test immunotherapies and elucidate treatment resistance mechanisms. The development of 3D in vitro melanoma models that faithfully replicate the complexity of the TME and its interaction with the immune system will provide us with the technical tools to better understand ICI resistance and increase its efficacy, thereby improving personalized melanoma therapy.

Abstract LB_C17: Spatial tumor immune microenvironment analysis of KRAS-mutated Non-Small Cell Lung Cancer and immunotherapy outcome

Abstract Targeting KRAS in lung cancer is promising and the immune modulatory effects of KRAS inhibition is interesting. Understanding the local tumor immune architectures are important to overcome the treatment resistance of immunotherapy and targeted therapy. We conducted spatial immune tumor microenvironment (iTME) profiling using FFPE samples of 25 KRAS mutated non-small cell lung cancer patients treated with immune checkpoint inhibitors (ICIs), which included 12 responders and 13 non-responders. We used an eleven-markers panel (CD3, CD4, CD8, Foxp3, CD68, Arginase-1, CD33, HLA-DR, Pan-Keratin (PanCK), PD-1 and PD-L1). We studied the tumor and immune cell compositions and spatial features at single cell level with cellular neighborhood and fractal analysis. We found spatial features and the different subgroups of CD68 positive cells and Foxp3+ cells associated with responses and resistance to ICIs. We found that CD68+ cells, CD33+ cells and Foxp3+ cells are associated with resistance to ICIs of KRAS mutated lung cancer. Interestingly, we found that cells had non-nuclear expression of Foxp3 were associated with ICIs resistance. We identified a population of CD68 weakly positive cells in the tumor tissues were associated with responses to ICIs. We identified two different groups of non-responders: one with high diversity of cells and one with low diversity, while all the responders had high diversity. We identified nine cellular neighborhoods (C0-C8) with C0 in majority of non-responders, which was enriched with PanCK+, CD33+, and Foxp3+ T regulartory cells. Conversely, most responders were enriched with C3 and C6-C7, which contained CD8+ T cells and CD68 weakly positive cells. Our study had revealed the spatial immune features of KRAS mutated lung cancer and their association with immunotherapy outcome which could be helpful for KRAS targeting and immunotherapy. Citation Format: Dan Zhao, Haiqing Li, Isa Mambetsariev, Tamara Mirzapoiazova, Chen Chen, Jeremy Fricke, Deric Wheeler, Leonidas Arvanitis, Raju Pillai, Michelle Afkhami, Bihong T. Chen, Martin Sattler, Loretta Erhunmwunsee, Erminia Massarelli, Prakash Kulkarni, Arya Amini, Brian Armstrong, Ravi Salgi. Spatial tumor immune microenvironment analysis of KRAS-mutated Non-Small Cell Lung Cancer and immunotherapy outcome [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C17.

Phase I/II trial of BMS-986,205 and nivolumab as first line therapy in hepatocellular carcinoma

BackgroundIndoleamine-2,3-dioxygenase (IDO) helps orchestrate immune suppression and checkpoint inhibitor resistance in hepatocellular carcinoma (HCC). BMS-986,205 is a novel oral drug that potently and selectively inhibits IDO. This Phase I/II study evaluated the safety and tolerability of BMS-986,205 in combination with nivolumab as first-line therapy in advanced HCC.MethodsAdults with untreated, unresectable/metastatic HCC received BMS-986,205 at two dose levels (50–100 mg orally daily) in combination with fixed dose nivolumab (240mg/m2 IV on Day 1 of each 14-day cycle). The primary objective was to determine the safety and tolerability of this combination; secondary objectives were to obtain preliminary efficacy.ResultsEight patients received a total of 91 treatment cycles in the dose escalation phase. All patients were Child Pugh A and 6 patients had underlying viral hepatitis. In the 6 evaluable patients, no dose-limiting toxicities (DLTs) were observed. The most common treatment-related adverse events (TRAEs) were aspartate transaminase (AST) and alanine transaminase (ALT) elevation (3 patients) and diarrhea, maculopapular rash and increased alkaline phosphatase (2 patients each). Grade 3 events were diarrhea and AST elevation (1 patient), and hyperglycemia and pancreatitis requiring treatment discontinuation (1 patient). No grade 4–5 events occurred. Partial response was observed in 1 patient (12.5%) and stable disease in 3 patients (37.5%), yielding a disease control rate of 50%. Median PFS was 8.5 weeks; median OS was not reached.ConclusionCombination BMS-986,205 and nivolumab showed a manageable safety profile with durable benefit as first-line therapy in a meaningful subset of advanced HCC patients.

Gut microbiome predicts gastrointestinal toxicity outcomes from chemoradiation therapy in patients with head and neck squamous cell carcinoma

ObjectivesChemoradiation (CRT) in patients with locally advanced head and neck squamous cell cancer (HNSCC) is associated with significant toxicities, including mucositis. The gut microbiome represents an emerging hallmark of cancer and a potentially important biomarker for CRT-related adverse events. This prospective study investigated the association between the gut microbiome composition and CRT-related toxicities in patients with HNSCC, including mucositis. Materials and methodsStool samples from patients diagnosed with locally advanced HNSCC were prospectively collected prior to CRT initiation and analyzed using shotgun metagenomic sequencing to evaluate gut microbiome composition at baseline. Concurrently, clinicopathologic data, survival outcomes and the incidence and grading of CRT-emergent adverse events were documented in all patients. ResultsA total of 52 patients were included, of whom 47 had baseline stool samples available for metagenomic analysis. Median age was 62, 83 % patients were men and 54 % had stage III-IV disease. All patients developed CRT-induced mucositis, including 42 % with severe events (i.e. CTCAE v5.0 grade ≥ 3) and 25 % who required enteral feeding. With a median follow-up of 26.5 months, patients with severe mucositis had shorter overall survival (HR = 3.3, 95 %CI 1.0–10.6; p = 0.02) and numerically shorter progression-free survival (HR = 2.8, 95 %CI, 0.8–9.6; p = 0.09). The gut microbiome beta-diversity of patients with severe mucositis differed from patients with grades 1–2 mucositis (p = 0.04), with enrichment in Mediterraneibacter (Ruminococcus gnavus) and Clostridiaceae family members, including Hungatella hathewayi. Grade 1–2 mucositis was associated with enrichment in Eubacterium rectale, Alistipes putredinis and Ruminococcaceae family members. Similar bacterial profiles were observed in patients who required enteral feeding. ConclusionPatients who developed severe mucositis had decreased survival and enrichment in specific bacteria associated with mucosal inflammation. Interestingly, these same bacteria have been linked to immune checkpoint inhibitor resistance.

Genetic and immune landscape evolution in MMR-deficient colorectal cancer.

Mismatch repair-deficient (MMRd) colorectal cancers (CRCs) have high mutation burdens, which make these tumours immunogenic and many respond to immune checkpoint inhibitors. The MMRd hypermutator phenotype may also promote intratumour heterogeneity (ITH) and cancer evolution. We applied multiregion sequencing and CD8 and programmed death ligand 1 (PD-L1) immunostaining to systematically investigate ITH and how genetic and immune landscapes coevolve. All cases had high truncal mutation burdens. Despite pervasive ITH, driver aberrations showed a clear hierarchy. Those in WNT/β-catenin, mitogen-activated protein kinase, and TGF-β receptor family genes were almost always truncal. Immune evasion (IE) drivers, such as inactivation of genes involved in antigen presentation or IFN-γ signalling, were predominantly subclonal and showed parallel evolution. These IE drivers have been implicated in immune checkpoint inhibitor resistance or sensitivity. Clonality assessments are therefore important for the development of predictive immunotherapy biomarkers in MMRd CRCs. Phylogenetic analysis identified three distinct patterns of IE driver evolution: pan-tumour evolution, subclonal evolution, and evolutionary stasis. These, but neither mutation burdens nor heterogeneity metrics, significantly correlated with T-cell densities, which were used as a surrogate marker of tumour immunogenicity. Furthermore, this revealed that genetic and T-cell infiltrates coevolve in MMRd CRCs. Low T-cell densities in the subgroup without any known IE drivers may indicate an, as yet unknown, IE mechanism. PD-L1 was expressed in the tumour microenvironment in most samples and correlated with T-cell densities. However, PD-L1 expression in cancer cells was independent of T-cell densities but strongly associated with loss of the intestinal homeobox transcription factor CDX2. This explains infrequent PD-L1 expression by cancer cells and may contribute to a higher recurrence risk of MMRd CRCs with impaired CDX2 expression. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Resistance to immune checkpoint inhibitors in gastric cancer.

Gastric cancer (GC) is one of the most common gastrointestinal malignancies worldwide. In the past decade, with the development of early diagnostic techniques, a clear decline in GC incidence has been observed, but its mortality remains high. The emergence of new immunotherapies such as immune checkpoint inhibitors (ICIs) has changed the treatment of GC patients to some extent. However, only a small number of patients with advanced GC have a durable response to ICI treatment, and the efficacy of ICIs is very limited. Existing studies have shown that the failure of immunotherapy is mainly related to the development of ICI resistance in patients, but the understanding of the resistance mechanism is still insufficient. Therefore, clarifying the mechanism of GC immune resistance is critical to improve its treatment and clinical benefit. In this review, we focus on summarizing the mechanisms of primary or acquired resistance to ICI immunotherapy in GC from both internal and external aspects of the tumor. At the same time, we also briefly discuss some other possible resistance mechanisms in light of current studies.

The progress of research on immune checkpoint inhibitor resistance and reversal strategies for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in humans, which is prone to recurrence and metastasis and has a poor prognosis. The occurrence and progression of HCC are closely related to immune elimination, immune homeostasis, and immune escape of the immune system. In recent years, immunotherapy, represented by immune checkpoint inhibitors (ICIs), has shown powerful anti-tumor capabilities in HCC patients. However, there are still some HCC patients who cannot benefit from ICIs treatment due to their innate or acquired drug resistance. Therefore, it is of great practical significance to explore the possible mechanisms of resistance to ICIs in HCC and to use them as a target to design strategies to reverse resistance, to overcome drug resistance in HCC and to improve the prognosis of patients. This article summarizes the possible primary (tumor microenvironment alteration, and signaling pathways, etc.) and acquired (immune checkpoint upregulation) resistance mechanisms in patients with HCC treated with ICIs, and based on this, discusses the status and effectiveness of combination drug strategy to reverse drug resistance, to provide a reference for subsequent related studies and decisions.

Immunocheckpoint Inhibitors in Microsatellite-Stable or Proficient Mismatch Repair Metastatic Colorectal Cancer: Are We Entering a New Era?

Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancer-related deaths in Europe. About 5% of metastatic CRC (mCRC) are characterized by high microsatellite instability (MSI) due to a deficient DNA mismatch repair (dMMR), and this condition has been related to a high sensitivity to immunotherapy, in particular to the Immune Checkpoint Inhibitors (ICIs). In fact, in MSI-H or dMMR mCRC, treatment with ICIs induced remarkable response rates and prolonged survival. However, the majority of mCRC cases are mismatch-repair-proficient (pMMR) and microsatellite-stable (MSS), and unfortunately these conditions involve resistance to ICIs. This review aims to provide an overview of the strategies implemented to overcome ICI resistance and/or define subgroups of patients with MSS or dMMR mCRC who may benefit from immunotherapy.

The microbial metabolite desaminotyrosine enhances T-cell priming and cancer immunotherapy with immune checkpoint inhibitors

Inter-individual differences in response to immune checkpoint inhibitors (ICI) remain a major challenge in cancer treatment. The composition of the gut microbiome has been associated with differential ICI outcome, but the underlying molecular mechanisms remain unclear, and therapeutic modulation challenging. We established an invivo model to treat C57Bl/6j mice with the type-I interferon (IFN-I)-modulating, bacterial-derived metabolite desaminotyrosine (DAT) to improve ICI therapy. Broad spectrum antibiotics were used to mimic gut microbial dysbiosis and associated ICI resistance. We utilized genetic mouse models to address the role of host IFN-I in DAT-modulated antitumour immunity. Changes in gut microbiota were assessed using 16S-rRNA sequencing analyses. We found that oral supplementation of mice with the microbial metabolite DAT delays tumour growth and promotes ICI immunotherapy with anti-CTLA-4 or anti-PD-1. DAT-enhanced antitumour immunity was associated with more activated T cells and natural killer cells in the tumour microenvironment and was dependent on host IFN-I signalling. Consistent with this, DAT potently enhanced expansion of antigen-specific T cells following vaccination with an IFN-I-inducing adjuvant. DAT supplementation in mice compensated for the negative effects of broad-spectrum antibiotic-induced dysbiosis on anti-CTLA-4-mediated antitumour immunity. Oral administration of DAT altered the gut microbial composition in mice with increased abundance of bacterial taxa that are associated with beneficial response to ICI immunotherapy. We introduce the therapeutic use of an IFN-I-modulating bacterial-derived metabolite to overcome resistance to ICI. This approach is a promising strategy particularly for patients with a history of broad-spectrum antibiotic use and associated loss of gut microbial diversity. Melanoma Research Alliance, Deutsche Forschungsgemeinschaft, German Cancer Aid, Wilhelm Sander Foundation, Novartis Foundation.

TIM-3 Expression and M2 Polarization of Macrophages in the TGFβ-Activated Tumor Microenvironment in Colorectal Cancer.

TGFβ signaling in the tumor microenvironment (TME) drives immune evasion and is a negative predictor of immune checkpoint inhibitor (ICI) efficacy in colorectal cancer (CRC). TIM-3, an inhibitory receptor implicated in anti-tumor immune responses and ICI resistance, has emerged as an immunotherapeutic target. This study investigated TIM-3, M2 macrophages and the TGFβ-activated TME, in association with microsatellite instability (MSI) status and consensus molecular subtypes (CMSs). Transcriptomic cohorts of CRC tissues, organoids and xenografts were examined (n = 2240). TIM-3 and a TGFβ-inducible stromal protein, VCAN, were evaluated in CRC specimens using immunohistochemistry (n = 45). TIM-3 expression on monocytes and generated M2 macrophages was examined by flow cytometry. We found that the expression of HAVCR2 (TIM-3) significantly correlated with the transcriptional signatures of TGFβ, TGFβ-dependent stromal activation and M2 macrophage, each of which were co-upregulated in CMS4, CMS1 and MSI CRCs across all datasets. Tumor-infiltrating TIM-3+ immune cells accumulated in TGFβ-responsive cancer stroma. TIM-3 was increased on M2-polarized macrophages, and on monocytes in response to TGFβ treatment. In conclusion, we identified a close association between TIM-3 and M2-like polarization of macrophages in the TGFβ-rich TME. Our findings provide new insights into personalized immunotherapeutic strategies based on the TME for CRCs.

Enzyme-mediated depletion of methylthioadenosine restores Tcell function in MTAP-deficient tumors and reverses immunotherapy resistance.

Chromosomal region 9p21 containing tumor suppressors CDKN2A/B and methylthioadenosine phosphorylase (MTAP) is one of the most frequent genetic deletions in cancer. 9p21 loss is correlated with reduced tumor-infiltrating lymphocytes (TILs) and resistance to immune checkpoint inhibitor (ICI) therapy. Previously thought to be caused by CDKN2A/B loss, we now show that it is loss of MTAP that leads to poor outcomes on ICI therapy and reduced TIL density. MTAP loss causes accumulation of methylthioadenosine (MTA) both intracellularly and extracellularly and profoundly impairs Tcell function via the inhibition of protein arginine methyltransferase 5 (PRMT5) and by adenosine receptor agonism. Administration of MTA-depleting enzymes reverses this immunosuppressive effect, increasing TILs and drastically impairing tumor growth and importantly, synergizes well with ICI therapy. As several studies have shown ICI resistance in 9p21/MTAP null/low patients, we propose that MTA degrading therapeutics may have substantial therapeutic benefit in these patients by enhancing ICI effectiveness.