CPI Resistance Mechanisms in Cancer Therapy

A beautiful study: Cracking the Code of Immunotherapy Resistance: How Chromosome 9p Loss Shapes Tumor Immune Evasion and a new cancer vaccine Original publication https://lnkd.in/gee5GMUP https://lnkd.in/g5naXTZh Background • Immune-checkpoint therapy (ICT) has revolutionized cancer treatment, but many patients fail to respond due to immune-evasive (“cold”) tumors. • Identifying non-responders and resistance mechanisms is essential for precision oncology. Key Findings 1. Chromosome 9p Loss as a Driver of ICT Resistance • In head and neck cancers (especially HPV-associated), loss of one or both copies of chromosome 9p was found to be the strongest driver of immune evasion. • This discovery has since been confirmed across lung, mesothelioma, melanoma, and bladder cancers. • Loss of 9p correlates with profound suppression of CXCL9/10 chemokines, essential for recruiting activated T cells to the tumor microenvironment. 2. Type-I Interferon (IFN-I) Genes Identified as the Culprit • New study pinpoints loss of IFN-I genes (17 in total, located on 9p21.2–21.3) as the mechanism behind ICT resistance. • IFN-I deficiency creates an immune-desert state, depleting CXCL9/10-producing immune cells and reducing T-cell infiltration. • Among these, IFNε was highlighted as a key, previously underappreciated regulator. 3. Not by Chance: Evolutionary Selection • Analysis showed homozygous deletions of 9p occur more frequently than expected, suggesting strong selective pressure for loss of interferon genes as an immune evasion strategy. Clinical Implications • Diagnostic Impact: Findings have led to Medicare-covered ICT-predictive tests for 9p loss, helping identify likely non-responders. • Therapeutic Innovation: • Researchers developed a dendritic-cell (DC) vaccine to bypass CXCL9/10 depletion and reprogram the tumor microenvironment. • Preclinical mouse models show promise, though human trials are still needed. • Future Strategy: Incorporating IFN-I/CXCL9/10 pathways into treatment design may personalize ICT and improve outcomes in resistant cancers Diagram shows mechanism of CXCL9/10 dendritic cell vaccine. Figure Credit: Scott Lippman, Catherine Eng and UCSD.

Hot Topic of the Week:  Surface Antigen Camouflage and Antigen Expression Loss Tumors often use complex mechanisms to evade immune detection, two of which are surface antigen camouflage and loss of antigen expression. These evasion strategies weaken the immune system's ability to recognize and eliminate cancer cells, and therefore pose a major challenge to immunotherapy. (1) Surface antigen camouflage mechanism Cancer cells can mask their antigens by changing or hiding the molecular structure on their surface. Glycosylation is a key mechanism, in which cancer cells modify their surface proteins by adding sugar molecules to mask the recognition of immune cells. In addition, cancer cells can also use overexpression of surface molecules such as CD47 (known as the "don't eat me" signal) to inhibit macrophage-mediated phagocytosis. This camouflage protects tumors from immune surveillance and creates an immune-tolerant microenvironment. (2) Loss of antigen expression Tumors can evade immune detection by downregulating or completely losing the expression of key tumor-associated antigens (TAAs) or tumor-specific antigens (TSAs). This mechanism is particularly common in T cell-mediated immune responses, as T cells rely primarily on antigen presentation to recognize and attack cancer cells. The loss of antigen expression may occur through mutation, epigenetic modification, or selection pressure of immune response, resulting in the inability of antigen-presenting cells to effectively detect tumor cells. This phenomenon is also the main reason for the resistance of immunotherapies such as CAR-T cells targeting specific antigens. Taken together, these immune evasion strategies together highlight the dynamic interaction between cancer cells and the immune system. Understanding these mechanisms can provide important help in the development of next-generation immunotherapies. For example, scientists can choose to target glycosylation pathways, enhance antigen presentation, or design new CAR-T cells to recognize a wider range of antigens, bringing hope to overcome immune resistance. References [1] Anoop Kallingal et al., J Cancer Res Clin Oncol 2023 (doi: 10.1007/s00432-023-04737-8) [2] Kailin Yang et al., Nature Reviews Clinical Oncology 2023 (https://lnkd.in/e7j2Apah) #ImmuneEvasion #CancerImmunotherapy #AntigenCamouflage #TumorResistance #CAR_Therapy #ImmunoOncology #CancerResearch #InnovationInMedicine #TumorMicroenvironment

Patients who initially respond to immune checkpoint inhibitors (ICIs) often relapse. Here, we studied how disease-progressive (DP) clinical melanomas evolve genomically to acquire ICI resistance. Compared to patient-matched pretreatment tumors, DP tumors recurrently amplified and/or deleted anti-apoptotic and/or pro-apoptotic genes, respectively. By chronic exposure to killer T cells or ICI therapy, we derived acquired-resistant (AR) human melanoma cell lines and murine melanoma tumors that recapitulate co-occurrent copy-number variants (CNVs) of apoptotic genes observed in DP melanomas. AR and DP subclones expanded shared, private, and, in some subclones, preexistent driver CNVs. Compared to isogenic parental cells, AR melanoma cells attenuated apoptotic priming but, with overexpression of deleted pro-apoptotic genes, recovered mitochondrial priming and sensitivity to killer T cells or ICIs. In mice, pharmacologically reducing the apoptotic threshold of ICI persisters prevented relapses. Thus, CNVs can drive the evolution of resistance to ICIs in melanoma, with tumor cell-intrinsic apoptotic threshold representing a target to curtail persister evolution. Paper and research by @Mingming Wu and larger team at UCLA

My article of the week. Those involved in oncology drug development and clinical practice are likely familiar with checkpoint inhibitors (CPIs) and their dramatic role in the battle against cancer. But, resistance to CPIs such as anti-PD-1 and anti-PD-L1 remains a significant challenge in the treatment of many solid tumours. Patients who fail CPI therapy have few alternative treatment options, highlighting a high unmet need. My article of the week explores GDF-15 (growth differentiation factor 15), a tumour-derived cytokine, as a potential driver of immune evasion and resistance to CPI therapies. Elevated GDF-15 levels are associated with reduced T-cell infiltration and impaired tumour immune response. Mechanism: The study identifies multiple mechanisms by which GDF-15 suppresses the immune response in the tumour microenvironment. GDF-15 affects it by: • Reducing T-cell recruitment and activation. • Modulating chemokine expression and immune surveillance pathways. • Inhibiting both innate and adaptive immune responses required for effective CPI treatment. Therapeutic Approach: The study investigated visugromab, a monoclonal antibody targeting GDF-15. Preclinical models demonstrated increased T-cell infiltration and enhanced anti-tumour activity when GDF-15 was neutralised. Combination therapy with CPI showed synergistic effects, overcoming immune suppression in resistant tumour models. Clinical Data: These findings translated into promising early clinical data. Preliminary clinical results in patients with refractory non-small cell lung cancer (NSCLC) and urothelial carcinoma showed: • Increased T-cell infiltration in tumour biopsies. • Durable responses in a subset of patients previously unresponsive to CPI therapies. This study highlights a new avenue to address CPI resistance by targeting GDF-15, that should be watched carefully #CheckpointInhibitors #CancerResearch #ImmunoOncology #DrugDevelopment #ClinicalInnovation

#ScienceSaturday ❓ Why do some cancers resist anti-PD-1 immunotherapy? ➡️ A new study in Nature Magazine shows that cancer-induced nerve injury (CINI) drives resistance. Tumors that damage nearby nerves trigger chronic inflammation, creating an immune-suppressive environment that blunts checkpoint blockade. ➡️ Importantly, targeting nerve injury pathways — such as blocking IL-6 signaling — helped restore response in models, pointing to new strategies to overcome resistance. 🌟 Congratulations to co-corresponding author Kenneth Tsai of Moffitt Cancer Center, collaborators at MD Anderson Cancer Center and others for advancing this critical field. 🔗 Read more: https://lnkd.in/ebtV7Cxb #CancerResearch #Immunotherapy #CheckpointBlockade #Neuroimmunology

Anti-PD-1/PD-L1 antibodies effectively fight tumors by reversing immune evasion and T-cell exhaustion, but drug resistance limits their effectiveness in many patients. This resistance is due to poor T-cell infiltration, lack of PD-1 expression, impaired interferon signaling, loss of tumor antigen presentation, and abnormal lipid metabolism. To combat this, researchers are developing combination therapies, some already clinically approved, such as ICIs with chemotherapy and targeted therapy. The review examines resistance mechanisms related to the tumor microenvironment, gut microbiota, epigenetic regulation, and co-inhibitory receptors, and explores combination strategies like traditional Chinese medicine, non-coding RNAs, targeted therapy, other ICIs, and personalized vaccines. It also highlights biomarkers predicting resistance and the success of combination therapies, advocating for personalized treatment based on biomarker systems to expand immunotherapy. #cancer #immunotherapy #resistance #combinations #chemotherapy #targetedtherapy