TY - JOUR
T1 - Neoantigen-specific cytotoxic Tr1 CD4 T cells suppress cancer immunotherapy
AU - Sultan, Hussein
AU - Takeuchi, Yoshiko
AU - Ward, Jeffrey P.
AU - Sharma, Naveen
AU - Liu, Tian Tian
AU - Sukhov, Vladimir
AU - Firulyova, Maria
AU - Song, Yuang
AU - Ameh, Samuel
AU - Brioschi, Simone
AU - Khantakova, Darya
AU - Arthur, Cora D.
AU - White, J. Michael
AU - Kohlmiller, Heather
AU - Salazar, Andres M.
AU - Burns, Robert
AU - Costa, Helio A.
AU - Moynihan, Kelly D.
AU - Yeung, Yik Andy
AU - Djuretic, Ivana
AU - Schumacher, Ton N.
AU - Sheehan, Kathleen C.F.
AU - Colonna, Marco
AU - Allison, James P.
AU - Murphy, Kenneth M.
AU - Artyomov, Maxim N.
AU - Schreiber, Robert D.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/8/1
Y1 - 2024/8/1
N2 - CD4+ T cells can either enhance or inhibit tumour immunity. Although regulatory T cells have long been known to impede antitumour responses1–5, other CD4+ T cells have recently been implicated in inhibiting this response6,7. Yet, the nature and function of the latter remain unclear. Here, using vaccines containing MHC class I (MHC-I) neoantigens (neoAgs) and different doses of tumour-derived MHC-II neoAgs, we discovered that whereas the inclusion of vaccines with low doses of MHC-II-restricted peptides (LDVax) promoted tumour rejection, vaccines containing high doses of the same MHC-II neoAgs (HDVax) inhibited rejection. Characterization of the inhibitory cells induced by HDVax identified them as type 1 regulatory T (Tr1) cells expressing IL-10, granzyme B, perforin, CCL5 and LILRB4. Tumour-specific Tr1 cells suppressed tumour rejection induced by anti-PD1, LDVax or adoptively transferred tumour-specific effector T cells. Mechanistically, HDVax-induced Tr1 cells selectively killed MHC-II tumour antigen-presenting type 1 conventional dendritic cells (cDC1s), leading to low numbers of cDC1s in tumours. We then documented modalities to overcome this inhibition, specifically via anti-LILRB4 blockade, using a CD8-directed IL-2 mutein, or targeted loss of cDC2/monocytes. Collectively, these data show that cytotoxic Tr1 cells, which maintain peripheral tolerance, also inhibit antitumour responses and thereby function to impede immune control of cancer.
AB - CD4+ T cells can either enhance or inhibit tumour immunity. Although regulatory T cells have long been known to impede antitumour responses1–5, other CD4+ T cells have recently been implicated in inhibiting this response6,7. Yet, the nature and function of the latter remain unclear. Here, using vaccines containing MHC class I (MHC-I) neoantigens (neoAgs) and different doses of tumour-derived MHC-II neoAgs, we discovered that whereas the inclusion of vaccines with low doses of MHC-II-restricted peptides (LDVax) promoted tumour rejection, vaccines containing high doses of the same MHC-II neoAgs (HDVax) inhibited rejection. Characterization of the inhibitory cells induced by HDVax identified them as type 1 regulatory T (Tr1) cells expressing IL-10, granzyme B, perforin, CCL5 and LILRB4. Tumour-specific Tr1 cells suppressed tumour rejection induced by anti-PD1, LDVax or adoptively transferred tumour-specific effector T cells. Mechanistically, HDVax-induced Tr1 cells selectively killed MHC-II tumour antigen-presenting type 1 conventional dendritic cells (cDC1s), leading to low numbers of cDC1s in tumours. We then documented modalities to overcome this inhibition, specifically via anti-LILRB4 blockade, using a CD8-directed IL-2 mutein, or targeted loss of cDC2/monocytes. Collectively, these data show that cytotoxic Tr1 cells, which maintain peripheral tolerance, also inhibit antitumour responses and thereby function to impede immune control of cancer.
UR - http://www.scopus.com/inward/record.url?scp=85199378535&partnerID=8YFLogxK
U2 - 10.1038/s41586-024-07752-y
DO - 10.1038/s41586-024-07752-y
M3 - Article
C2 - 39048822
AN - SCOPUS:85199378535
SN - 0028-0836
VL - 632
SP - 182
EP - 191
JO - Nature
JF - Nature
IS - 8023
ER -