ACIR

D’Alise and Willis et al. presented results from a phase 1b/2 single-arm trial of 45 Lynch syndrome (LS) carriers treated with Nous-209 – an IM, heterologous, prime/boost, virus-based vaccine encoding 209 frameshift peptides (FSPs) shared across neoplasms with microsatellite instability (MSI). Potent/durable vaccine-induced FSP-specific IFNγ-producing CD4+ and cytotoxic CD8+ T cell responses were observed in all 37 evaluable participants. Peptide–HLA predictions helped identify >100 FSPs, which were immunogenic in vitro and detected in datasets of LS MSI-high colorectal pre-cancers/cancers. The vaccine was safe, and no participants had advanced adenomas or CRC at the end of the study. bit.ly/41bz8C9 @NouscomS @MDAndersonNews @evilarsan

ROR1 CAR T cells infiltrated ROR1+ NSCLC mouse tumors, but lost TCF1 expression and failed to maintain a progenitor exhausted (Tpex) population. The addition of anti-PD-L1 did not improve CAR T cell counts or efficacy, and further drove exhaustion. Snyder et al. found that co-delivery of c-Jun by the ROR1 CAR transiently increased CAR-T tumor accumulation and Tpex phenotype, and combining with anti-PD-L1 further improved tumor T cell counts, c-Jun expression, phenotype, and efficacy. Spatial transcriptomics found that c-Jun CAR-T were distributed throughout lung tumors, proximal to PD-L1+ myeloid cells, and Tpex-enriched relative to standard CAR-T. bit.ly/4bgJjLE  @fredhutch

To improve anti-angiogenic therapies in VEGF-overexpressing solid tumors, Gao et al. engineered CAR T cells to secrete anti-VEGF scFvs (CAR-αVEGF T cells) and compared their efficacy with standard CAR T cell therapy alone or combined with anti-VEGF Ab. αVEGF-scFv secretion resulted in superior CAR T cell efficacy in ovarian cancer and orthotopic glioma models. Mechanistically, CAR-αVEGF T cells prevented treatment-induced angiogenesis and hypoxia, promoted CD8+ T cell activation and mitochondrial fitness, and boosted immune-stimulatory myeloid phenotypes, while decreasing infiltration of suppressive, VEGF-expressing myeloid cells. bit.ly/4bOEGZj  @UCLAHealthJCCC

Chi et al. engineered a recyclable PD-L1 degrader (RECYC) by fusing a moderate-affinity peptide binder of PD-L1 to an aptamer against the ubiquitous endolysosomal trafficking receptor CI-M6PR. RECYC robustly degraded PD-L1 in tumor and myeloid cells, and exhibited pH-sensitive dissociation from PD-L1, enabling repeated knockdown following membrane recycling. I.v. RECYC outperformed anti-PD-L1 in multiple tumor models. and drove greater PD-L1 knockdown in tumor and myeloid cells, which correlated with efficacy. RECYC enhanced T cell infiltration and early activation, and uniquely promoted M1/N1-like skewing in tumor-associated macrophages and neutrophils. bit.ly/4tcID07

While TOX in CD8+ T cells is associated with exhaustion and poor prognosis, recent work by Naizir et al. showed the opposite effect in CD4+ T cells, where TOX expression was associated with TH1 differentiation, effector function, antitumor immunity, and autoimmune pathology. bit.ly/4rI2Vgt @SchietingerLab @BriannaNaizir @WeizmannScience

Wang and Cao et al. focused on how TAMs contribute to tumor progression. An immunosuppressive CD19+ macrophage subpopulation, associated with poor clinical outcomes, was enriched in HCC and many other cancer types. These cells exhibited increased levels of PD-L1 and CD73, enhanced mitochondrial oxidation, and deficient phagocytosis. Mechanistically, PAX5 drove mitochondrial biogenesis in CD19+ TAMs, depleting cytosolic Ca2+, leading to lysosomal deficiency and accumulation of PD-L1 and CD73. Targeting CD19+ TAMs with CD19-specific CAR T cells, anti-CD73, or OXPHOS inhibitors enhanced the efficacy of checkpoint blockade therapy in HCC models. bit.ly/4db9IvG

Hanina et al. demonstrated that CD70 is heterogeneously expressed in solid tumors ranging to ultra-low, due to epigenetic silencing of CD70 by EZH2-mediated H3K27 trimethylation. Conventional detection assays were unable to detect ultra-low levels of CD70, and commonly used CARs failed to achieve complete tumor clearance. A more sensitive CD70-targeted CAR T cell utilizing a VH/VL-engineered HLA-independent T cell receptor (HIT) eradicated heterogeneous tumors, without additional toxicity, in xenograft models of multiple cancers. An epigenetic signature based on CD70 chromatin accessibility detected ultra-low expression and HIT sensitivity. bit.ly/3NdszM8

Register now for On Demand Access to @KeystoneSymp #CancerImmunotherapy : Mechanisms, Clinical Advances and Combinations to explore emerging research! bit.ly/4sv4Tlu #KSCancerImmune26

Dominik and Victoria et al. identified NR2F6 as a T cell-intrinsic metabolic checkpoint for CAR T cells in solid tumors. CRISPR/Cas9-mediated deletion of NR2F6 sustained a TCF1+ progenitor exhausted state and maintained metabolic fitness during chronic antigen stimulation. NR2F6 deletion in CAR T cells increased cytotoxicity, cytokine production, resistance to functional exhaustion, and tumor control in immunocompetent Panc02-EpCAM tumor models. DC-mediated cross-priming with epitope spreading and activation of endogenous immunity generated durable protection against CAR antigen-positive and -negative tumor rechallenge. bit.ly/4bnAb6Q

Frischholz et al. analyzed CD8+ T cells after yellow fever vaccination, and found that TEM and TCM phenotypes dominated the acute response at 14 days. However, a naive-like T memory population (TNM) comprised ~50% of the repertoire at 1 year, and remained for decades post-vaccination. At 14 days, TNM were characterized by quiescence, downregulated effector programs, low proliferation, and minimal apoptosis. This was in contrast to TCM, cycling, and effector-like populations, which contracted within 1-2 months. While all T cells primarily leveraged oxidative phosphorylation, TCM uniquely leveraged glycolysis, and TNM exclusively utilized OXPHOS. bit.ly/40psyHW

Nie, Liu, Yao, et al. developed an erythrocyte–antibody conjugate in which anti-PD-1 antibodies were covalently linked to erythrocyte membranes (αPD1-Ery). These cellular-Ab conjugates accumulated in spleens, where they expanded effector T cells and reduced immunosuppressive myeloid cells, leading to reduced tumor growth in mouse models. In a first-in-human phase I clinical trial, 14 patients with advanced cancers who were resistant to anti-PD-1/L1 were treated at 2 dose levels, which were well tolerated and reduced circulating immunosuppressive myeloid cells. The ORR was 42.9%, with 1 CR and 5 PRs, and the DCR was 78.6%. bit.ly/4rsEljP

Finding that CCR7 was downregulated during CAR T manufacturing, Zschummel et al. generated CAR T cells with CCR7 overexpression (CAR.CCR7). Compared to CAR-T, CAR.CCR7-T had increased CCL19-mediated migration in vitro, and demonstrated LN accumulation and lymphoma depletion in a syngeneic mouse model. CAR.CCR7-T had superior cytotoxicity in vitro compared to standard CAR-T, especially at low E:T, but not due to CAR or Th1 cytokine expression, or the ligand CCL19. CAR.CCR7-T cells were larger, had increased cytoskeletal regulatory gene expression, recruited CCR7 to the immune synapse, and showed early ZAP70 phosphorylation and degranulation. bit.ly/4ljaCIs  @MGHInstitute

mRNA vaccine trial in TNBC bit.ly/4sCKJWD  @BioNTech_Group 👉 Sahin, Schmidt, et al. conducted a clinical study of patients with early-stage TNBC who were treated with a personalized neoantigen mRNA vaccine strategy following standard therapy. Durable neoantigen-specific CD8+ and CD4+ T cell responses were detected, with 10/14 patients remaining relapse-free during long-term follow-up. Several resistance mechanisms were uncovered in three patients with recurrences; a weak vaccine-induced response, recurrence related to the primary tumor not used for vaccine creation, and downregulation of antigen presentation in tumor cells.

What if immune cells don't need to destroy a cell to learn from it? Max Krummel's talk at #AACRio26 quietly reframed how we think about myeloid cell surveillance. His team observed macrophages picking up tiny pinched-off vesicles from living cells — a trogocytosis-like "nibbling" — without killing them. The sampled material then traveled through a distinct intracellular pathway, bypassing the usual route to lysosomes. The striking finding: this live-sampling pathway drove efficient MHC class I presentation and CD8+ T cell stimulation — arguably better than classical phagocytosis. The implication? Live-cell sampling may be the default mode of immune surveillance, with phagocytosis as the exception. And tumors may hijack this very pathway to drive T cell exhaustion. It's the kind of fundamental biology that quietly reshapes everything downstream. 🔬 🔗 Read ACIR's full #AACRio26 special feature → bit.ly/4sjXuoL #CancerImmunology #Immunotherapy #AACR #MyeloidCells @MaxKrummel

Could antidepressants become cancer immunotherapy? Lili Yang's talk at #AACRio26 was one of the most surprising of the meeting. Her team discovered that the entire serotonin recycling pathway — normally associated with neurons — is active in tumor-infiltrating T cells. Serotonin produced after antigen stimulation acts as a brake on T cell activation. The twist: SSRIs (selective serotonin reuptake inhibitors), already widely prescribed for depression, enhanced T cell activity and synergized with anti-PD-1 in mouse models. The transcriptional profiles barely overlapped — suggesting these are genuinely complementary mechanisms. A clinical trial in neuroendocrine tumors is in the works. 👀 ACIR's full AACR IO special feature covers this and a dozen other cutting-edge talks. 🔗 bit.ly/4sjXuoL #CancerImmunotherapy #Immunooncology #DrugRepurposing @ucla

We are looking forward to covering this new exciting #CancerImmunotherapy : Mechanisms, Clinical Advances and Combinations meeting, March 15-18 in Québec with @KeystoneSymp! Take a look at their impressive line-up and register for On Demand access: bit.ly/4sv4Tlu #KSCancerImmune26

🧬 T cells are being pushed far beyond what evolution designed them for. At #AACRio26, Phil Greenberg revealed why T cells fail in pancreatic tumors — and the clever strategies his team is using to fight back: switch receptors that flip inhibitory signals into stimulatory ones, engineered CD4+ T cells that prevent exhaustion, and a newly identified E3 ligase (Klhl6) that keeps T cells functional and mitochondria healthy. In early clinical results with KRAS G12V TCR-engineered T cells, two of the first three patients showed tumor shrinkage 📉 This is what it looks like to engineer around evolution. 🔗 Read ACIR's full coverage of #AACRio26 →bit.ly/4sjXuoL  @hutchgreenberg

Adams et al. identified Etv3 as a dendritic cell-intrinsic regulator of immune tolerance. Etv3 is induced during DC maturation and expressed in tissue-derived migratory DCs (migDCs). Etv3 cooperated with NF-κB to promote homeostatic migDC maturation and CCR7-dependent migration. Etv3 deficiency impaired migDC migration and induced upregulation of costimulatory molecules (including OX40L), driving dysfunctional CD25low Treg expansion, spontaneous T cell activation, and multi-organ inflammation. Loss of Etv3 worsened TLR7-driven systemic lupus erythematosus (SLE)-like disease, consistent with observations in human SLE. bit.ly/40tywaz  @NickAdams_PhD  @nyugrossman

Genetic studies by Li et al. showed that SLAMF6 (also known as Ly108) functioned to repress T cell activation in mice and humans by triggering homotypic cis interactions at the T cell surface, suppressing TCR signaling through SHP-1 and limiting antitumor immunity, independent of SLAMF6 expression on tumor cells or APCs. SLAMF6 was expressed preferentially on Tpex cells, but not terminally exhausted Tex cells, and potent agonist mAbs that blocked T cell SLAMF6 cis binding boosted T cell activation and increased antitumor T cell responses, decreased numbers of Tex cells, and inhibited tumor growth in vivo, comparable to results obtained with SLAMF6 deficiency. bit.ly/4cMNik4  @mcgillu

To support more sensitive immunopeptidomics analyses, Manakongtreecheep and Ctortecka et al. developed Pepyrus to rapidly and scalably generate user-defined peptide libraries in E. coli that could provide chromatographic and spectral references. Papyrus-enabled data-independent acquisition (DIA) allowed sensitive and high-confidence detection of lower-affinity and less abundant clinically relevant HLA-bound peptides, including neoantigens in complex patient samples. Further, a spectral library encompassing HIF-inducible ERVs for a renal cell carcinoma sample was reused “off-the-shelf” to analyze a melanoma sample, and identified ERV-derived peptides. bit.ly/3MIGzNI  @BroadProteomics  @ClaudiaCtor  @danaFarber