Immune Checkpoint Inhibitors in Tumor Microenvironment Research

Immune checkpoint blockade (ICB) therapy has transformed cancer treatment, yet many patients fail to respond. Employing single-cell multiomics, we unveil T cell dynamics influencing ICB response across 480 pan-cancer and 27 normal tissue samples. We identify four immunotherapy response-associated T cells (IRATs) linked to responsiveness or resistance and analyze their pseudotemporal patterns, regulatory mechanisms, and T cell receptor clonal expansion profiles specific to each response. Notably, transforming growth factor β1 (TGF-β1)+ CD4+ and Temra CD8+ T cells negatively correlate with therapy response, in stark contrast to the positive response associated with CXCL13+ CD4+ and CD8+ T cells. Validation with a cohort of 23 colorectal cancer (CRC) samples confirms the significant impact of TGF-β1+ CD4+ and CXCL13+ CD4+ and CD8+ T cells on ICB efficacy. Our study highlights the effectiveness of single-cell multiomics in pinpointing immune markers predictive of immunotherapy outcomes, providing an important resource for crafting targeted immunotherapies for successful ICB treatment across cancers. Interesting new study in Cell Press Reports Medicine: https://lnkd.in/e69kDM2d

New Nature Portfolio Medicine paper: A pan-cancer foundation model predicts immunotherapy response and reveals the biology behind it https://lnkd.in/dCK-v-hj HMS News: https://lnkd.in/dwkDpufy Roughly a quarter of patients with cancer respond durably to immune checkpoint inhibitors. The rest endure toxicity and cost with little benefit, and existing tools, TMB, PD-L1 staining, remain unreliable across cancer types and drugs Concept bottleneck architecture for tumor immune microenvironment COMPASS encodes each tumor transcriptome, then routes it through a transformer bottleneck aggregated into interpretable immune and stromal concepts before predicting response. It reasons through human-readable biology instead of latent features Self-supervised pretraining, then cohort-specific fine-tuning COMPASS is pretrained on 10,184 tumors across 33 cancer types to learn generalizable tumor-immune representations before any treatment outcome, then tuned on clinical cohorts, with strategies from zero-shot inference to full updates, calibrated to cohort size Outperforms 22 biomarkers and predictive models In leave-one-cohort-out evaluation, COMPASS beat 22 methods, with the highest generalization rate in cohort-to-cohort transfer Generalizes across cancer types, therapies, and checkpoint targets Withholding an entire cancer type, drug class, or checkpoint target during training, performance held up on the excluded category. It predicted combination therapy response when trained only on monotherapy cohorts Multi-stage fine-tuning for early-phase trial design Early trials enroll small populations with limited target-specific data, complicating indication selection. Pretraining on pan-cancer data, then general ICI cohorts, then a single target drug, outperformed single-stage approaches for atezolizumab, pembrolizumab, and nivolumab, which could help trial runners prioritize indications before large efficacy data exist Survival stratification beats TMB and PD-L1 immunohistochemistry In a held-out phase 2 atezolizumab trial in metastatic urothelial carcinoma, COMPASS-classified responders survived longer than non-responders (HR = 4.7), exceeding TMB and PD-L1 scoring Personalized response maps uncover resistance within immune phenotypes Tracing predictions through its concept hierarchy, COMPASS identified resistance mechanisms among immune-inflamed non-responders, including TGFβ-driven immunosuppression, vascular exclusion, and CD4+ T cell and B cell deficiency, resolving cases where phenotyping alone would have predicted response incorrectly Fantastic work by Wanxiang Shen, Intae Moon, Thinh H. Nguyen, Michelle M. Li, Yepeng Huang, Nitya Nair, Daniel Marbach Harvard Medical School Department of Biomedical Informatics Harvard Medical School Roche Harvard University Broad Institute of MIT and Harvard Kempner Institute at Harvard University

Here’s How to Prime Tumors to be Defeated by Cancer Immunotherapy UCSF research may green light many more patients for immunotherapy, offering a faster path to remission and relief. The study reexamined immunotherapy clinical trial data on bladder and skin cancer and found that “cold” tumors, ones that haven’t yet been infiltrated by immune cells, are just as vulnerable to checkpoint inhibitors as “hot” tumors, which have. In mice, these cold tumors were defeated with a combination of radiation, immunotherapy and drugs that block a signal, TGF-Beta. Tumors use this signal to evade the immune system. The findings were published on March 6 in the Journal for ImmunoTherapy of Cancer. Identification of a conserved subset of cold tumors responsive to immune checkpoint blockade Results We found that a high βAlt score predicts ICB response yet is paradoxically associated with an immune-poor tumor microenvironmentcancer in both human and mouse tumors. We postulated that high βAlt cancers consist of cancer cells in which loss of TGFβ signaling generates a TGFβ rich, immunosuppressive tumor microenvironment. Accordingly, preclinical modeling showed that TGFβ inhibition followed by radiotherapy could convert an immune-poor, high βAlt tumor to an immune-rich, ICB-responsive tumor. Mechanistically, TGFβ inhibition increased activated natural killer (NK) cells, which were required to recruit lymphocytes to respond to ICB in irradiated tumors. NK cell activation signatures were also increased in high βAlt, cold mouse and human tumors that responded to ICB. Conclusions These studies indicate that loss of TGFβ signaling competency and gain of error-prone DNA repair identifies a subset of cold tumors that are responsive to ICB. Our mechanistic studies show that inhibiting TGFβ activity can convert a high βAlt, cold tumor into ICB-responsive tumors via NK cells. A biomarker consisting of combined TGFβ, DNA repair, and immune context signatures is a means to prospectively identify patients whose cancers may be converted from cold to hot with appropriate therapy. https://lnkd.in/eapunhTE

In this article, I explore new insights into how different immune checkpoint inhibitor (ICI) combinations affect CD8+ T cell behavior in cancer immunotherapy. A recent clinical trial from a US research team compared the efficacy of anti-PD-1 monotherapy, anti-PD-1+CTLA-4, and anti-PD-1+LAG-3 combination therapy in patients with head and neck cancer, revealing different immune dynamics. Notably, anti-PD-1+LAG-3 therapy reprogrammed exhausted CD8+ T cells into more functional memory types and promoted a wider range of T cell receptor (TCR) diversity; while anti-PD-1+CTLA-4 therapy mainly expanded existing memory T cells without rejuvenating exhausted T cells. These findings highlight the association between specific T cell clones and transcriptional shifts and better treatment responses and provide new biomarkers for treatment selection. Join us to explore the need for personalized immunotherapy strategies based on T cell behavior and immune microenvironment characteristics. #CancerImmunotherapy #CD8Tcells #CheckpointInhibitors #TCellClonality #PrecisionOncology #LAG3 #CTLA4 #ImmunoOncology #TCRdiversity #ScienceNewsletter #CSTEAMBiotech

Cracking #Solid Tumor #Barriers with PD-L1–Directed #CAR T Cells The efficacy of chimeric antigen receptor (CAR)-T cells in the context of solid tumors is #constrained, in part, by the #immunosuppressive #characteristics of the tumor microenvironment (#TME). To enhance antitumor responses, John K. Lee, Lawrennce A. Stern, Saul Priceman, Carl June, and their collaborators posited that the ability of CAR-T cells to secrete #bifunctional fusion proteins, which comprise a #cytokine modifier such as TGFβtrap, IL-15, or IL-12, in #conjunction with an immune checkpoint #inhibitor such as αPD-L1, would facilitate tumor-localized #immunomodulation, thereby #augmenting CAR-T cell functionality. In the present investigation, the authors have #engineered CAR-T cells to secrete #molecules of TGFβtrap, IL-15, or IL-12 fused to αPD-L1 scFv and have evaluated their in vitro #functionality as well as their in vivo safety and efficacy within #prostate and #ovarian cancer models. CAR-T cells modified to express αPD-L1–IL-12 demonstrate #enhanced safety and efficacy relative to both unmodified CAR-T cells and those engineered with αPD-L1 fused to TGFβtrap or IL-15. Furthermore, αPD-L1–IL-12 engineered CAR-T cells #facilitate improved T cell #trafficking and tumor infiltration, while also localizing IFNγ production, TME modulation, and #antitumor responses, with a concomitant reduction in systemic inflammation-associated toxicities. The authors propose that the αPD-L1–IL-12 engineering #strategy represents a significant opportunity to #enhance the clinical efficacy and safety of CAR-T cells across a variety of solid tumor types. Authors & Institutes : John P. Murad. | Lea Christian | Reginaldo Rosa, MBA, PhD | Yuwei Ren | Alyssa J. Buckley | John K. Lee | Lawrence A. Stern |  Saul Priceman  |  Carl June | Keck School of Medicine of the University of Southern California | City of Hope | The Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University | Emory University School of Medicine | University of Pennsylvania Perelman School of Medicine Figure courtesy & more information: https://lnkd.in/gQTBBPcQ #cart #immunotherapy #cellandgenetherapy #celltherapy #immunology #solidtumor #immunooncology #genetherapy #cartcelltherapy #oncology

The FMT-LUMINate phase 2 trial evaluated fecal microbiota transplantation (FMT) from healthy donors combined with immune checkpoint inhibitors in treatment-naive patients: 20 with non-small cell lung cancer (NSCLC) receiving anti-PD-1 monotherapy, and 20 with melanoma receiving dual anti-PD-1 plus anti-CTLA-4 therapy. Primary endpoint (NSCLC): An 80% objective response rate (ORR) was achieved, exceeding the prespecified 64% threshold. The disease control rate was 95%, with median one-year progression-free survival of 65% and one-year overall survival of 100%. Secondary endpoint (Melanoma): A 75% ORR was observed, with four complete responses and 11 partial responses. One-year progression-free survival was 58% and overall survival was 79%. These response rates substantially exceed historical benchmarks of 39-46% for anti-PD-1 monotherapy in NSCLC and 50-58% for dual checkpoint inhibition in melanoma. FMT proved well-tolerated in the NSCLC cohort with no grade 3 or higher adverse events. However, the melanoma cohort experienced earlier-onset toxicity, with 65% of melanoma patients developing grade 3+ adverse events and 15% experiencing myocarditis. These severe toxicities clustered exclusively in recipients of FMT from donors enriched in Prevotella species, and only in the dual immunotherapy context—not in patients receiving anti-PD-1 monotherapy. The engraftment of Prevotella copri was associated with an increased proportion of a subset of CD4+ T cells in the peripheral blood of patients. Some Prevotella species may prime or over-activate these T cells, leading to a systemic inflammatory state. Unlike previous assumptions, clinical response was not driven by engraftment of donor-derived bacterial strains or increased donor-recipient microbiota similarity. Instead, responders exhibited significantly greater loss of baseline bacterial species compared to non-responders. Responders consistently lost deleterious bacteria including Enterocloster citroniae, E. lavalensis, and Clostridium innocuum. This depletion pattern was validated across three published FMT oncology trials, demonstrating reproducibility. Responders exhibited decreased tryptophan pathway metabolites (quinolinic acid and kynurenine), which are associated with immunosuppression. High bacterial loss correlated with increased circulating CD8+ effector T cells and reduced regulatory T cells—a favorable immunometabolic profile. The study emphasizes that donor selection must be rationally designed based on the specific immunotherapy a patient is receiving, paving the way for personalized adjunct microbiome therapies. Source: Duttagupta, S., Messaoudene, M., Hunter, S. et al. Fecal microbiota transplantation plus immunotherapy in non-small cell lung cancer and melanoma: the phase 2 FMT-LUMINate trial. Nat Med (2026). doi:10.1038/s41591-025-04186-5

💫 We are thrilled to share the first hard-core immunology paper from the Batlle Lab, now published in Nature Genetics!  Very proud of the team and efforts behind it. The study was led by Ana Henriques, Maria Salvany Celades, and Alejandro Prados, in my lab, in collaboration with many outstanding colleagues at IRB Barcelona and Paula Nieto and Holger Heyn at Centro Nacional de Análisis Genómico (CNAG). ➡️ Together we unravel how TGF-β signaling builds a dual immune barrier in colorectal cancer metastases. Kudos to all 👏 🙌 🔝 We had previously shown (Tauriello et al, Nature 2018) that blocking TGF-β synergizes with immunotherapy to eradicate colorectal cancer metastases. In this new work, we dove into the immunology of metastatic disease to understand why this happens. 💡 Key findings: ✅        TGF-β acts directly on T cells, preventing the recruitment of peripheral memory CD8⁺ T cells into liver metastases. ✅         Inhibition of TGF-β signaling restores both T cell infiltration and clonal expansion, converting resistant tumors into responders to anti–PD-L1 therapy. ✅        Clonal expansion is inhibited indirectly through reprogramming of tumor-associated macrophages to express SPP1 (osteopontin), which shapes a fibrotic and immunosuppressive niche. ✅        The SPP1-driven environment prevents infiltrated T cells from proliferating, effectively. ✅         In the absence of osteopontin, immune checkpoint blockade efficacy is increased. ✅       anti–PD-L1 therapy boosted T cell motility allowing infiltrated cells to move and engage targets. Together, these findings reveal how TGF-β orchestrates immune evasion across both innate and adaptive immune compartments — and point to new strategies to improve immunotherapy outcomes in colorectal cancer. 👉 Read the full article: Henriques et al., Nature Genetics (2025) “TGF-β builds a dual immune barrier in colorectal cancer by impairing T cell recruitment and instructing immunosuppressive SPP1 macrophages.” https://lnkd.in/dzZmqi_c WE thank all funding agencies: This research was supported by the European Research Council (ERC), Asociación Española Contra el Cáncer, Fundación ”la Caixa”, Worldwide Cancer Research, La Marató de TV3 3Cat Corporatiu CIBERONC, AGAUR, Fundación Olga Torres, and the Spanish Ministerio de Ciencia, Innovación y Universidades . #ColorectalCancer #Immunotherapy #TGFbeta #CancerResearch #NatureGenetics #IRBBarcelona #CNAG #TranslationalResearch #IRBBarcelona

Cancer just showed us its playbook - and it’s nastier than we thought. UC San Diego scientists discovered why so many patients don’t respond to today’s most celebrated cancer drugs, immune checkpoint therapies. It isn’t random. Tumors are literally rewriting their own DNA to cut the phone lines that call in killer T-cells. No 9p arm of the chromosome. No interferon signals. No T-cells. No fight. That’s why so many tumors look “cold” and shrug off therapy. They’ve evolved an escape hatch. But here’s where it gets fascinating: the same team turned that weakness into an opening. They engineered a vaccine to flip the switch back on - restoring the immune signals, waking up the tumor microenvironment, and pulling T-cells back into the fight. In mice, it worked. Human trials are on the horizon. So what’s next? If this holds up, it doesn’t just patch a gap in cancer care. It rewrites the playbook - from testing who’s likely to resist therapy, to reprogramming tumors that were once untouchable. Imagine if “non-responders” became responders. How many lives, how many markets, how many clinical strategies does that change overnight?

#ScienceSaturday ❓ What if we could outsmart cancer that no longer responds to immunotherapy? ➡️ A recent study in Nature Biotech introduces an innovative way to reawaken the immune system against metastatic melanoma that has become resistant to checkpoint inhibitors. ➡️ Researchers engineered tiny, naturally occurring particles called exosomes to act as immune “decoys.” These exosomes carry two key signals at once: one that removes the brakes cancer puts on T cells, and another that helps immune cells actually enter the tumor. Delivered by inhalation, the therapy homes in on lung metastases while limiting exposure to the rest of the body. ➡️ In multiple mouse models, including humanized models, this approach restored immune cell infiltration, reduced tumor growth, and outperformed standard antibody-based immunotherapy, all with a favorable safety profile. The findings point to a promising new strategy for tackling cancers that have learned how to hide from the immune system. 🌟 Congratulations to the research team for advancing a smarter, more targeted approach to cancer immunotherapy! Columbia University Irving Medical Center Columbia University Nature Portfolio Nature Magazine 🔗 Read the full study in Nature Biotechnology: https://lnkd.in/ekkAXn8H