# Tumor-specific CD8+ Tc9 cells activate host CD4+ T cells to control antigen-lost tumors

> **NIH NIH R01** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2024 · $489,857

## Abstract

PROJECT SUMMARY
Adoptive cell transfer using tumor-specific T cells is a promising option for cancer treatment and the most
powerful tumor-killing effector T cells are CD8+ type-1 cytotoxic T cells (Tc1). We have shown that IL-9-
secreting CD8+ Tc9 cells mediate stronger and long-lasting antitumor effects in vivo compared to the classical
IFN-γ-secreting Tc1. However, the underlying mechanisms remain unclear. Recently, we discovered that,
when we rechallenged Pmel-1 Tc9- or Tc1-treated mice on the contralateral flank with gp100-knockout (KO)
B16 tumor cells, these cells rapidly grew and established tumors in Tc1 but not Tc9-treated mice. Similarly,
relapsed gp100– B16 cells recovered from Pmel-1 Tc1-treated mice rapidly grew and established tumors after
re-implanting to Pmel-1 Tc1- but not Tc9-treated mice, suggesting that Tc9- but not Tc1-treated mice develop a
host immunity against other (than the cognate) antigens expressed by relapsed tumors. Importantly,
significantly larger numbers of CD4+ but not CD8+ T cells were detected in late-stage tumors, rechallenged
tumors and tumor-draining lymph nodes (TDLNs) of Tc9-treated mice compared to Tc1-treated mice. These
CD4+ T cells expressed high levels of IFNγ and granzyme-B and effectively killed wild-type B16, gp100–
relapsed and gp100-KO B16 tumor cells. Hence, these novel findings strongly indicate that adoptively
transferred Tc9 but not Tc1 cells effectively induce a host CD4+ T cell response against relapsed tumors. To
determine the mechanism underlying Tc9 cell-induced host CD4+ T cell response, we performed preliminary
studies to examine immune cells in tumor microenvironment (TME). We observed that dendritic cells (DCs)
were enriched in Tc9-treated primary tumors, rechallenged tumors, and TDLNs. More importantly, Tc9 cells
secreted a high level of IL-24, and Tc9-treated tumor supernatants contained abundant IL-24. As our
preliminary studies showed that IL-24 attracted DC migration in vitro, we speculate that Tc9 cells induce a host
CD4+ T cell response through IL-24-DC circuit. We hypothesize that tumor-specific Tc9 cells may be a superb
T-cell subset for cancer immunotherapy due to their capacity to elicit a host CD4+ T cell response to suppress
the growth of relapsed tumors. To test our hypothesis, Aim 1 will determine the role and importance of Tc9 cell-
induced host CD4+ T cell responses in recognizing and eliminating relapsed tumor cells, and Aim 2 will
determine the role and mechanism of IL-24-DC circuit in TME and TDLNs in eliciting tumor-specific CD4+ T cell
responses and preventing the recurrence of tumors. Completing this project will uncover a novel mechanism of
Tc9 cells in mediating long-lasting antitumor activity in TME by inducing host CD4+ T cells to recognize tumor-
associated antigens or neoantigens via IL-24-DC circuit and suppressing or preventing tumor recurrence in
Tc9-treated mice.

## Key facts

- **NIH application ID:** 10764129
- **Project number:** 1R01CA285209-01
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** Qing Yi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $489,857
- **Award type:** 1
- **Project period:** 2024-01-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764129

## Citation

> US National Institutes of Health, RePORTER application 10764129, Tumor-specific CD8+ Tc9 cells activate host CD4+ T cells to control antigen-lost tumors (1R01CA285209-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10764129. Licensed CC0.

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