Abstract A006: Tumor-specific MHC-II shapes an inflamed immune and stromal microenvironment in clear cell renal cell carcinoma

Abstract Tumor-specific MHC-II (tsMHC-II) expression has been associated with superior prognosis, increased T cell infiltration, and improved response to anti–PD-1 immunotherapy across multiple cancer types, but its role in renal cell carcinoma (RCC) remains poorly defined. This study asked how tsMHC-II expression in RCC tumor cells remodels the immune and stromal microenvironment and how an MHC-II gene signature associates with clinical outcomes across treatment and immune-infiltration contexts. Single-cell RNA-seq with paired TCR-seq was performed on tumors from 30 patients with clear cell RCC. A tumor-cell MHC-II module score was generated using key HLA genes, and tumor cells were classified as MHC-II positive or negative using a Gaussian mixture model cutoff; MHC-II–high samples were defined as having more than 50% positive cells. Compositional differences were tested using multivariable models controlling for sample-level covariates, and pseudobulk CD4 T cell differential expression (FDR0. 05) defined MHC-II–associated transcriptional programs. The same MHC-II signature was scored in a bulk RNA-seq RCC cohort (R2000, n=2, 026), and Cox models tested associations between signature expression and survival within strata of immune infiltration (CIBERSORT) and treatment class (ICI–based regimens versus VEGF TKIs). Despite minimal CD80/CD86 on tumor cells, MHC-II–high tumors showed expansion of CD4 T cells (P=0. 03, fold change=1. 68) with enrichment of naïve and memory-like subsets and a relative reduction in regulatory T cells. CD8 T cell fractions were similar overall but shifted toward proliferating and naïve phenotypes in MHC-II–high tumors. MHC-II–high tumors also had increased CD56bright NK cells (P=0. 04, fold change=2. 36) and ACTG2-positive pericytes (P=0. 009, fold change=1. 58), whereas MHC-II–low tumors were enriched for fibroblasts (P=0. 03, fold change=1. 17), including myCAF/vCAF-like subsets, consistent with an inflamed yet structurally permissive stroma. Pseudobulk CD4 T cells from MHC-II–high tumors upregulated genes linked to T follicular/helper-like and central memory programs together with multiple immune checkpoints, indicating coexisting effector and regulatory states. In the R2000 cohort, higher MHC-II signature expression was associated with reduced hazard of death in highly immune-infiltrated tumors treated with VEGF TKIs and with improved progression-free survival specifically in below-median immune infiltration tumors treated with ICIs. Because bulk RNA-seq captures both tumor and immune compartments, stratifying by inferred immune infiltration was used to enrich, respectively, for samples with higher or lower proportions of non-immune (and thus putative tumor) cells, supporting that the “cold”-tumor association reflects tumor-cell rather than purely immune-cell MHC-II expression. These data show that tsMHC-II in RCC defines an immunologically active state with coordinated remodeling of adaptive, innate, and stromal compartments and that the impact of an MHC-II program on outcomes is strongly treatment- and immune-context dependent. Citation Format: Ruchi Gupta, Ro Malik, Zhaochen Ye, Rishabh Rout, Soki Kashima, David Braun. Tumor-specific MHC-II shapes an inflamed immune and stromal microenvironment in clear cell renal cell carcinoma abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₂): Abstract nr A006.