# PIK3C2A is a vulnerable immunotherapeutic target in triple-negative breast cancer combination therapy

> **NIH NIH F30** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $48,068

## Abstract

PROJECT SUMMARY
Treatment options for triple-negative breast cancer (TNBC) have been very limited. However, specific molecular
features such as high PD-L1 expression, elevated tumor mutational burden, and increased tumor infiltrating
lymphocytes in the tumor immune microenvironment (TIME) make TNBC an ideal candidate for immune
checkpoint blockade (ICB)-based therapy. Poor clinical response of TNBC to the ICB monotherapy necessitates
the identification of novel targets capable of enhancing the anti-tumor effects of immunotherapy. Effective
cytotoxic T cell (CTL)-mediated immune responses against cancer cells rely on adequate tumor antigen
presentation (AP). Insufficient tumor AP compromises the efficacy of ICB therapies, presenting a significant
obstacle in solid tumor immunotherapy. Enhancing surface MHC-I expression emerges as a plausible strategy
to potentiate ICB-based immunotherapy. Genetic alterations in the antigen processing and presentation (APP)
machinery or dysregulations in the intrinsic endolysosomal network are the main causes of diminished tumor
AP. While genetic alterations in the APP machinery have been extensively studied, factors regulating the
endolysosomal network in tumor AP remain underexplored. Our laboratory utilized the “Inference of Cell Types
and Deconvolution” algorithm and identified PIK3C2A as a promising druggable target in TNBC cells that
regulates phosphoinositide metabolism. Depletion of PIK3C2A in TNBC cells demonstrated significant
upregulation of tumor AP and enhanced cytotoxicity of specific CD8+ T cells. We hypothesize that inhibition of
PIK3C2A alters PI(3,4)P2 metabolism, resulting in dysfunctional endocytic vesicle formation, preventing the
internalization of the antigen:MHC-I complex, and thereby increasing the tumor AP. PIK3C2A is a dual-function
protein with both kinase and non-kinase activities. Its kinase activity regulates the endocytosis pathway through
PI(3,4)P2 generation around the neck of endocytic vesicles. Conversely, the non-kinase function of PIK3C2A
prevents chromosomal instability. Due to this dual functionality, the exact molecular mechanism contributing to
enhanced tumor AP remains unclear. The overall goal of this project is to characterize the function of PIK3C2A
in TNBC cells and its impact on the TNBC TIME. Aim 1 will elucidate the mechanism underpinning enhanced
tumor AP upon PIK3C2A depletion in TNBC cells through transcriptomic profiling, PI(3,4)P2 quantification, and
examining the Ova/MHC-I turnover rate in vitro. In Aim 2, we will use a PIK3C2A isoform-selective inhibitor
(PITCOIN1) and anti-PD-1 combination to treat orthotopic TNBC tumors in syngeneic mouse model as a proof-
of-concept study to determine whether this combination therapy inflames the TIME and promotes potent tumor
regression in vivo. This project aligns with my training as a future physician-scientist, whose research goal is to
focus on the discovery and development of solid tumor immunotherapy.

## Key facts

- **NIH application ID:** 10997500
- **Project number:** 1F30CA294711-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Xiyu Wang
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,068
- **Award type:** 1
- **Project period:** 2024-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997500

## Citation

> US National Institutes of Health, RePORTER application 10997500, PIK3C2A is a vulnerable immunotherapeutic target in triple-negative breast cancer combination therapy (1F30CA294711-01). Retrieved via AI Analytics 2026-06-24 from https://api.ai-analytics.org/grant/nih/10997500. Licensed CC0.

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