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

Award Number: R01CA285209
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $440,870 )
2026	2026	THE METHODIST HOSPITAL RESEARCH INSTITUTE	6565 FANNIN ST STE D200	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	3	1/12/2026	NON-COMPETING CONTINUATION	$440,870
														Subtotal = $440,870

Issue Date FY: 2025 ( Subtotal = $489,857 )
2025	2025	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	2	11/19/2024	NON-COMPETING CONTINUATION	$440,870
2025	2025	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	2	6/6/2025	NON-COMPETING CONTINUATION	$48,987
														Subtotal = $489,857

Issue Date FY: 2024 ( Subtotal = $489,857 )
2024	2024	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	12/21/2023	NEW	$489,857
														Subtotal = $489,857

Grand Total All Awards = $1,420,584

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

Award Number: R01CA285209

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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