# Modulation of the anti-tumor immune response by Major Histocompatibility Class-II expression on tumor cells

> **NIH NIH F30** · VANDERBILT UNIVERSITY · 2020 · $49,775

## Abstract

PROJECT SUMMARY/ABSTRACT
Immune checkpoint inhibition (ICI) has improved the outlook for many patients with metastatic cancer. However,
resistance to ICI remains poorly understood, with no currently approved therapeutic strategies to overcome
resistance. A possible mechanism of resistance to ICI is ineffective recognition of a tumor by a T cell, which is
mediated by Major Histocompatibility Complex (MHC)-T cell receptor interactions. Most tumors express MHC
class I, which presents antigen to CD8+ T cells, which are thought to be the main cytotoxic effector cells.
Interestingly, a subset of tumors also express MHC class II, which presents antigen to CD4+ T cells and is
canonically thought to only be present on “professional” antigen presenting cells of the immune system. CD4+ T
cells are a diverse population and include helper subsets that are crucial generating and maintaining an effective
immune response. Our lab has shown that tumor-specific MHC-II (tsMHC-II) expression is a positive prognostic
indicator for melanoma patients treated with ICI. Additionally, our preliminary data show that enforced tumor cell
expression of Class II Major Histocompatibility Complex Transactivator (CIITA), which drives expression of MHC-
II and related machinery, enhances tumor rejection in immunocompetent mice. Additional preliminary co-culture
experiments suggest that CD4+ T cells produce more pro-inflammatory cytokine when stimulated with MHC-II+
compared to MHC-II- tumor cells. These data, in mouse and human, suggest that tsMHC-II may enhance anti-
tumor immunity through activation of helper T cells. Thus, we hypothesize that tsMHC-II can be recognized by
T cell receptors (TCRs) from CD4+ T cells, activates signaling in CD4+ T cells, and skews toward anti-tumor
polarization of CD4+ T cells. This proposal outlines two detailed specific aims for testing this hypothesis.
Proposed experiments include in vitro co-culture of tumor cells and T cells in order to isolate the phenotypic
change in CD4+T cells following engagement of tsMHC-II. In vivo murine models and mass cytometry-based
characterization of human tumors will further define how tsMHC-II alters the immune microenvironment.
Furthermore, we will generate solubilized TCRs (sTCRs) from CD4+ T cells infiltrating tsMHC-II+ tumors and
test the ability of these sTCRs to bind to autologous tsMHC-II+ tumor cells. We will also transduce these TCRs
into an immortalized T cell line to test the ability of tsMHC-II engagement to induce signaling changes in T cells.
Completion of this project will yield new insights regarding how tsMHC-II is recognized by autologous infiltrating
CD4+ T cells and how tsMHC-II influences anti-tumor CD4+ T cell responses. Overall, this project will enhance
understanding of anti-tumor immunity and may suggest novel translational approaches to circumventing
resistance to ICI in the clinic through tsMHC-II upregulating agents.

## Key facts

- **NIH application ID:** 10003813
- **Project number:** 5F30CA236157-02
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Margaret Axelrod
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $49,775
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003813

## Citation

> US National Institutes of Health, RePORTER application 10003813, Modulation of the anti-tumor immune response by Major Histocompatibility Class-II expression on tumor cells (5F30CA236157-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10003813. Licensed CC0.

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