Abstract 1204: Neoantigen MHC presentability ratios influence the tumor microenvironment and response to immunotherapy
Authors: Sears Timothy J. , Lee Ko-Han , Pagadala Meghana , Castro Andrea , Zanetti Maurizio , Carter Hannah 
Published: March 2024

Introduction: Recent literature suggests that neoantigens presented via MHC-II induce a CD4+ T Cell mediated immune response, and MHC-I presented neoantigens expand CD8+ cytotoxic T Cells populations. We developed an algorithm to stratify patients into MHC-I Reliant and MHC-II Reliant immune checkpoint blockade (ICB) responders.

Experimental Procedures: Our algorithm generates patient mean harmonic best rank scores (PHBR) of each neoantigen in a tumor to estimate the proportion of neoantigens that are likely well presented by each MHC complex, given a patient’s specific HLA alleles. From there, the ratio of neoantigens presented by each MHC (class-I and class-II) can be used to stratify patients into MHC-I or MHC-II Reliant groupings. The primary goals of our study were to investigate tumor immune microenvironment and survival differences between these groups. First, we used CIBERSORTx infiltration estimates of the ratio of these CD4/CD8 T cell populations across our MHC Reliance categories and by response vs nonresponse in two separate cohorts: Discovery (110) and Validation (77).

Results: We first observed that the CD4/CD8 ratio is higher in MHC-II responders than in MHC-I responders (Fig 6. A, P=~0.0057 Discovery; P=0.025 Validation), but no such a difference was found in nonresponders. Using an alternate digital cytometry tool (xCell) we obtained similar results (MHC-II vs MHC-I responders discovery P=0.44; validation P=0.0015) (Fig. S7). We applied an identical methodology to immune-hot ICB-naive cancer samples from TCGA and found that there was a powerful protective effect of the CD4/CD8 ratio in TCGA MHC-II Reliant patients (Fig S6. HR=-0.76, P=0.0092), there was a significantly harmful effect of that same ratio in TCGA MHC-I Reliant patients (Fig S6 HR=0.59, P=0.0352). These data demonstrate a benefit to having some level of concordance between CD4/CD8+ T cell infiltration and MHC-II/MHC-I neoantigen presentability ratios. Since CD4 memory based immune responses have a longer duration of action over more transient CD8 cytotoxic immune responses (cite), we compared the survival of responders in MHC-II vs MHC-I Reliance groups. MHC-II Reliant responders had a significantly longer overall survival in both discovery and validation cohorts (Fig 6. B-C, discovery P=0.0073; validation P=0.0398).

Conclusions: While neoantigens are already used in ICB stratification in the context of tumor mutational burden, we demonstrate that the balance of which MHC is presenting a set of neoantigens is relevant to immune infiltration and treatment outcome.

Citation Format: Timothy J. Sears, Ko-Han Lee, Meghana Pagadala, Andrea Castro, Maurizio Zanetti, Hannah Carter. Neoantigen MHC presentability ratios influence the tumor microenvironment and response to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1204.