Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation

Jaikumar Duraiswamy; Riccardo Turrini; Aspram Minasyan; David Barras; Isaac Crespo; Alizée J. Grimm; Julia Casado; Raphael Genolet; Fabrizio Benedetti; Alexandre Wicky; Kalliopi Ioannidou; Wilson Castro; Christopher Neal; Amandine Moriot; Stéphanie Renaud-Tissot; Victor Anstett; Noémie Fahr; Janos L. Tanyi; Monika A. Eiva; Connor A. Jacobson; Kathleen T. Montone; Marie Christine Wulff Westergaard; Inge Marie Svane; Lana E. Kandalaft; Mauro Delorenzi; Peter K. Sorger; Anniina Färkkilä; Olivier Michielin; Vincent Zoete; Santiago J. Carmona; Periklis G. Foukas; Daniel J. Powell; Sylvie Rusakiewicz; Marie Agnès Doucey; Denarda Dangaj Laniti; George Coukos

doi:10.1016/j.ccell.2021.10.008

Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation

Jaikumar Duraiswamy, Riccardo Turrini, Aspram Minasyan, David Barras, Isaac Crespo, Alizée J. Grimm, Julia Casado, Raphael Genolet, Fabrizio Benedetti, Alexandre Wicky, Kalliopi Ioannidou, Wilson Castro, Christopher Neal, Amandine Moriot, Stéphanie Renaud-Tissot, Victor Anstett, Noémie Fahr, Janos L. Tanyi, Monika A. Eiva, Connor A. JacobsonKathleen T. Montone, Marie Christine Wulff Westergaard, Inge Marie Svane, Lana E. Kandalaft, Mauro Delorenzi, Peter K. Sorger, Anniina Färkkilä, Olivier Michielin, Vincent Zoete, Santiago J. Carmona, Periklis G. Foukas, Daniel J. Powell, Sylvie Rusakiewicz, Marie Agnès Doucey, Denarda Dangaj Laniti, George Coukos^*

^*Corresponding author af dette arbejde

Center for Cancer Immune Therapy (CCIT), Department of Oncology, Copenhagen University Hospital , Herlev, Denmark.

76 Citationer (Scopus)

Abstract

The mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TIL) and responsiveness to PD-1 blockade remain partly unknown. In human ovarian cancer, we show that tumor-specific CD8⁺ TIL accumulate in tumor islets, where they engage antigen and upregulate PD-1, which restrains their functions. Intraepithelial PD-1⁺CD8⁺ TIL can be, however, polyfunctional. PD-1⁺ TIL indeed exhibit a continuum of exhaustion states, with variable levels of CD28 costimulation, which is provided by antigen-presenting cells (APC) in intraepithelial tumor myeloid niches. CD28 costimulation is associated with improved effector fitness of exhausted CD8⁺ TIL and is required for their activation upon PD-1 blockade, which also requires tumor myeloid APC. Exhausted TIL lacking proper CD28 costimulation in situ fail to respond to PD-1 blockade, and their response may be rescued by local CTLA-4 blockade and tumor APC stimulation via CD40L.

Originalsprog	Engelsk
Tidsskrift	Cancer Cell
Vol/bind	39
Udgave nummer	12
Sider (fra-til)	1623-1642.e20
ISSN	1535-6108
DOI	https://doi.org/10.1016/j.ccell.2021.10.008
Status	Udgivet - 13 dec. 2021

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10.1016/j.ccell.2021.10.008

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Duraiswamy, J., Turrini, R., Minasyan, A., Barras, D., Crespo, I., Grimm, A. J., Casado, J., Genolet, R., Benedetti, F., Wicky, A., Ioannidou, K., Castro, W., Neal, C., Moriot, A., Renaud-Tissot, S., Anstett, V., Fahr, N., Tanyi, J. L., Eiva, M. A., ... Coukos, G. (2021). Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation. Cancer Cell, 39(12), 1623-1642.e20. https://doi.org/10.1016/j.ccell.2021.10.008

Duraiswamy, J, Turrini, R, Minasyan, A, Barras, D, Crespo, I, Grimm, AJ, Casado, J, Genolet, R, Benedetti, F, Wicky, A, Ioannidou, K, Castro, W, Neal, C, Moriot, A, Renaud-Tissot, S, Anstett, V, Fahr, N, Tanyi, JL, Eiva, MA, Jacobson, CA, Montone, KT, Westergaard, MCW, Svane, IM, Kandalaft, LE, Delorenzi, M, Sorger, PK, Färkkilä, A, Michielin, O, Zoete, V, Carmona, SJ, Foukas, PG, Powell, DJ, Rusakiewicz, S, Doucey, MA, Dangaj Laniti, D & Coukos, G 2021, 'Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation', Cancer Cell, bind 39, nr. 12, s. 1623-1642.e20. https://doi.org/10.1016/j.ccell.2021.10.008

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title = "Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation",

abstract = "The mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TIL) and responsiveness to PD-1 blockade remain partly unknown. In human ovarian cancer, we show that tumor-specific CD8+ TIL accumulate in tumor islets, where they engage antigen and upregulate PD-1, which restrains their functions. Intraepithelial PD-1+CD8+ TIL can be, however, polyfunctional. PD-1+ TIL indeed exhibit a continuum of exhaustion states, with variable levels of CD28 costimulation, which is provided by antigen-presenting cells (APC) in intraepithelial tumor myeloid niches. CD28 costimulation is associated with improved effector fitness of exhausted CD8+ TIL and is required for their activation upon PD-1 blockade, which also requires tumor myeloid APC. Exhausted TIL lacking proper CD28 costimulation in situ fail to respond to PD-1 blockade, and their response may be rescued by local CTLA-4 blockade and tumor APC stimulation via CD40L.",

keywords = "CD28, CD40, CTLA-4, dendritic cell, exhaustion, myeloid niche, ovarian, PD-1, TIL, tumor",

author = "Jaikumar Duraiswamy and Riccardo Turrini and Aspram Minasyan and David Barras and Isaac Crespo and Grimm, {Aliz{\'e}e J.} and Julia Casado and Raphael Genolet and Fabrizio Benedetti and Alexandre Wicky and Kalliopi Ioannidou and Wilson Castro and Christopher Neal and Amandine Moriot and St{\'e}phanie Renaud-Tissot and Victor Anstett and No{\'e}mie Fahr and Tanyi, {Janos L.} and Eiva, {Monika A.} and Jacobson, {Connor A.} and Montone, {Kathleen T.} and Westergaard, {Marie Christine Wulff} and Svane, {Inge Marie} and Kandalaft, {Lana E.} and Mauro Delorenzi and Sorger, {Peter K.} and Anniina F{\"a}rkkil{\"a} and Olivier Michielin and Vincent Zoete and Carmona, {Santiago J.} and Foukas, {Periklis G.} and Powell, {Daniel J.} and Sylvie Rusakiewicz and Doucey, {Marie Agn{\`e}s} and {Dangaj Laniti}, Denarda and George Coukos",

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year = "2021",

month = dec,

day = "13",

doi = "10.1016/j.ccell.2021.10.008",

language = "English",

volume = "39",

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TY - JOUR

T1 - Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation

AU - Duraiswamy, Jaikumar

AU - Turrini, Riccardo

AU - Minasyan, Aspram

AU - Barras, David

AU - Crespo, Isaac

AU - Grimm, Alizée J.

AU - Casado, Julia

AU - Genolet, Raphael

AU - Benedetti, Fabrizio

AU - Wicky, Alexandre

AU - Ioannidou, Kalliopi

AU - Castro, Wilson

AU - Neal, Christopher

AU - Moriot, Amandine

AU - Renaud-Tissot, Stéphanie

AU - Anstett, Victor

AU - Fahr, Noémie

AU - Tanyi, Janos L.

AU - Eiva, Monika A.

AU - Jacobson, Connor A.

AU - Montone, Kathleen T.

AU - Westergaard, Marie Christine Wulff

AU - Svane, Inge Marie

AU - Kandalaft, Lana E.

AU - Delorenzi, Mauro

AU - Sorger, Peter K.

AU - Färkkilä, Anniina

AU - Michielin, Olivier

AU - Zoete, Vincent

AU - Carmona, Santiago J.

AU - Foukas, Periklis G.

AU - Powell, Daniel J.

AU - Rusakiewicz, Sylvie

AU - Doucey, Marie Agnès

AU - Dangaj Laniti, Denarda

AU - Coukos, George

PY - 2021/12/13

Y1 - 2021/12/13

N2 - The mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TIL) and responsiveness to PD-1 blockade remain partly unknown. In human ovarian cancer, we show that tumor-specific CD8+ TIL accumulate in tumor islets, where they engage antigen and upregulate PD-1, which restrains their functions. Intraepithelial PD-1+CD8+ TIL can be, however, polyfunctional. PD-1+ TIL indeed exhibit a continuum of exhaustion states, with variable levels of CD28 costimulation, which is provided by antigen-presenting cells (APC) in intraepithelial tumor myeloid niches. CD28 costimulation is associated with improved effector fitness of exhausted CD8+ TIL and is required for their activation upon PD-1 blockade, which also requires tumor myeloid APC. Exhausted TIL lacking proper CD28 costimulation in situ fail to respond to PD-1 blockade, and their response may be rescued by local CTLA-4 blockade and tumor APC stimulation via CD40L.

AB - The mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TIL) and responsiveness to PD-1 blockade remain partly unknown. In human ovarian cancer, we show that tumor-specific CD8+ TIL accumulate in tumor islets, where they engage antigen and upregulate PD-1, which restrains their functions. Intraepithelial PD-1+CD8+ TIL can be, however, polyfunctional. PD-1+ TIL indeed exhibit a continuum of exhaustion states, with variable levels of CD28 costimulation, which is provided by antigen-presenting cells (APC) in intraepithelial tumor myeloid niches. CD28 costimulation is associated with improved effector fitness of exhausted CD8+ TIL and is required for their activation upon PD-1 blockade, which also requires tumor myeloid APC. Exhausted TIL lacking proper CD28 costimulation in situ fail to respond to PD-1 blockade, and their response may be rescued by local CTLA-4 blockade and tumor APC stimulation via CD40L.

KW - CD28

KW - CD40

KW - CTLA-4

KW - dendritic cell

KW - exhaustion

KW - myeloid niche

KW - ovarian

KW - PD-1

KW - TIL

KW - tumor

UR - http://www.scopus.com/inward/record.url?scp=85120666851&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2021.10.008

DO - 10.1016/j.ccell.2021.10.008

M3 - Journal article

C2 - 34739845

AN - SCOPUS:85120666851

SN - 1535-6108

VL - 39

SP - 1623-1642.e20

JO - Cancer Cell

JF - Cancer Cell

IS - 12

ER -

Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation

Abstract

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