MCT4-dependent lactate secretion suppresses antitumor immunity in LKB1-deficient lung adenocarcinoma

Yu Qian; Ana Galan-Cobo; Irene Guijarro; Minghao Dang; David Molkentine; Alissa Poteete; Fahao Zhang; Qi Wang; Jing Wang; Edwin Parra; Apekshya Panda; Jacy Fang; Ferdinandos Skoulidis; Ignacio I. Wistuba; Svena Verma; Taha Merghoub; Jedd D. Wolchok; Kwok Kin Wong; Ralph J. DeBerardinis; John D. Minna; Natalie I. Vokes; Catherine B. Meador; Justin F. Gainor; Linghua Wang; Alexandre Reuben; John V. Heymach

doi:10.1016/j.ccell.2023.05.015

MCT4-dependent lactate secretion suppresses antitumor immunity in LKB1-deficient lung adenocarcinoma

Yu Qian, Ana Galan-Cobo, Irene Guijarro, Minghao Dang, David Molkentine, Alissa Poteete, Fahao Zhang, Qi Wang, Jing Wang, Edwin Parra, Apekshya Panda, Jacy Fang, Ferdinandos Skoulidis, Ignacio I. Wistuba, Svena Verma, Taha Merghoub, Jedd D. Wolchok, Kwok Kin Wong, Ralph J. DeBerardinis, John D. MinnaNatalie I. Vokes, Catherine B. Meador, Justin F. Gainor, Linghua Wang, Alexandre Reuben, John V. Heymach

Translational Molecular Pathology

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

Inactivating STK11/LKB1 mutations are genomic drivers of primary resistance to immunotherapy in KRAS-mutated lung adenocarcinoma (LUAD), although the underlying mechanisms remain unelucidated. We find that LKB1 loss results in enhanced lactate production and secretion via the MCT4 transporter. Single-cell RNA profiling of murine models indicates that LKB1-deficient tumors have increased M2 macrophage polarization and hypofunctional T cells, effects that could be recapitulated by the addition of exogenous lactate and abrogated by MCT4 knockdown or therapeutic blockade of the lactate receptor GPR81 expressed on immune cells. Furthermore, MCT4 knockout reverses the resistance to PD-1 blockade induced by LKB1 loss in syngeneic murine models. Finally, tumors from STK11/LKB1 mutant LUAD patients demonstrate a similar phenotype of enhanced M2-macrophages polarization and hypofunctional T cells. These data provide evidence that lactate suppresses antitumor immunity and therapeutic targeting of this pathway is a promising strategy to reversing immunotherapy resistance in STK11/LKB1 mutant LUAD.

Original language	English (US)
Pages (from-to)	1363-1380.e7
Journal	Cancer cell
Volume	41
Issue number	7
DOIs	https://doi.org/10.1016/j.ccell.2023.05.015
State	Published - Jul 10 2023

Keywords

immunotherapy resistance
lactate
LKB1
lung adenocarcinoma
macrophage polarization
MCT4
metabolism
PD-1
T cell activation

ASJC Scopus subject areas

Oncology
Cancer Research

MD Anderson CCSG core facilities

Bioinformatics Shared Resource

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10.1016/j.ccell.2023.05.015

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Qian, Y., Galan-Cobo, A., Guijarro, I., Dang, M., Molkentine, D., Poteete, A., Zhang, F., Wang, Q., Wang, J., Parra, E., Panda, A., Fang, J., Skoulidis, F., Wistuba, I. I., Verma, S., Merghoub, T., Wolchok, J. D., Wong, K. K., DeBerardinis, R. J., ... Heymach, J. V. (2023). MCT4-dependent lactate secretion suppresses antitumor immunity in LKB1-deficient lung adenocarcinoma. Cancer cell, 41(7), 1363-1380.e7. https://doi.org/10.1016/j.ccell.2023.05.015

Qian, Y , Galan-Cobo, A, Guijarro, I, Dang, M, Molkentine, D, Poteete, A, Zhang, F, Wang, Q, Wang, J , Parra, E, Panda, A, Fang, J, Skoulidis, F , Wistuba, II, Verma, S, Merghoub, T, Wolchok, JD, Wong, KK, DeBerardinis, RJ, Minna, JD, Vokes, NI, Meador, CB, Gainor, JF, Wang, L , Reuben, A & Heymach, JV 2023, 'MCT4-dependent lactate secretion suppresses antitumor immunity in LKB1-deficient lung adenocarcinoma', Cancer cell, vol. 41, no. 7, pp. 1363-1380.e7. https://doi.org/10.1016/j.ccell.2023.05.015

@article{e03663ae2ba544fb88689f6b5506e81a,

title = "MCT4-dependent lactate secretion suppresses antitumor immunity in LKB1-deficient lung adenocarcinoma",

abstract = "Inactivating STK11/LKB1 mutations are genomic drivers of primary resistance to immunotherapy in KRAS-mutated lung adenocarcinoma (LUAD), although the underlying mechanisms remain unelucidated. We find that LKB1 loss results in enhanced lactate production and secretion via the MCT4 transporter. Single-cell RNA profiling of murine models indicates that LKB1-deficient tumors have increased M2 macrophage polarization and hypofunctional T cells, effects that could be recapitulated by the addition of exogenous lactate and abrogated by MCT4 knockdown or therapeutic blockade of the lactate receptor GPR81 expressed on immune cells. Furthermore, MCT4 knockout reverses the resistance to PD-1 blockade induced by LKB1 loss in syngeneic murine models. Finally, tumors from STK11/LKB1 mutant LUAD patients demonstrate a similar phenotype of enhanced M2-macrophages polarization and hypofunctional T cells. These data provide evidence that lactate suppresses antitumor immunity and therapeutic targeting of this pathway is a promising strategy to reversing immunotherapy resistance in STK11/LKB1 mutant LUAD.",

keywords = "immunotherapy resistance, lactate, LKB1, lung adenocarcinoma, macrophage polarization, MCT4, metabolism, PD-1, T cell activation",

author = "Yu Qian and Ana Galan-Cobo and Irene Guijarro and Minghao Dang and David Molkentine and Alissa Poteete and Fahao Zhang and Qi Wang and Jing Wang and Edwin Parra and Apekshya Panda and Jacy Fang and Ferdinandos Skoulidis and Wistuba, {Ignacio I.} and Svena Verma and Taha Merghoub and Wolchok, {Jedd D.} and Wong, {Kwok Kin} and DeBerardinis, {Ralph J.} and Minna, {John D.} and Vokes, {Natalie I.} and Meador, {Catherine B.} and Gainor, {Justin F.} and Linghua Wang and Alexandre Reuben and Heymach, {John V.}",

note = "Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

year = "2023",

month = jul,

day = "10",

doi = "10.1016/j.ccell.2023.05.015",

language = "English (US)",

volume = "41",

pages = "1363--1380.e7",

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TY - JOUR

T1 - MCT4-dependent lactate secretion suppresses antitumor immunity in LKB1-deficient lung adenocarcinoma

AU - Qian, Yu

AU - Galan-Cobo, Ana

AU - Guijarro, Irene

AU - Dang, Minghao

AU - Molkentine, David

AU - Poteete, Alissa

AU - Zhang, Fahao

AU - Wang, Qi

AU - Wang, Jing

AU - Parra, Edwin

AU - Panda, Apekshya

AU - Fang, Jacy

AU - Skoulidis, Ferdinandos

AU - Wistuba, Ignacio I.

AU - Verma, Svena

AU - Merghoub, Taha

AU - Wolchok, Jedd D.

AU - Wong, Kwok Kin

AU - DeBerardinis, Ralph J.

AU - Minna, John D.

AU - Vokes, Natalie I.

AU - Meador, Catherine B.

AU - Gainor, Justin F.

AU - Wang, Linghua

AU - Reuben, Alexandre

AU - Heymach, John V.

PY - 2023/7/10

Y1 - 2023/7/10

N2 - Inactivating STK11/LKB1 mutations are genomic drivers of primary resistance to immunotherapy in KRAS-mutated lung adenocarcinoma (LUAD), although the underlying mechanisms remain unelucidated. We find that LKB1 loss results in enhanced lactate production and secretion via the MCT4 transporter. Single-cell RNA profiling of murine models indicates that LKB1-deficient tumors have increased M2 macrophage polarization and hypofunctional T cells, effects that could be recapitulated by the addition of exogenous lactate and abrogated by MCT4 knockdown or therapeutic blockade of the lactate receptor GPR81 expressed on immune cells. Furthermore, MCT4 knockout reverses the resistance to PD-1 blockade induced by LKB1 loss in syngeneic murine models. Finally, tumors from STK11/LKB1 mutant LUAD patients demonstrate a similar phenotype of enhanced M2-macrophages polarization and hypofunctional T cells. These data provide evidence that lactate suppresses antitumor immunity and therapeutic targeting of this pathway is a promising strategy to reversing immunotherapy resistance in STK11/LKB1 mutant LUAD.

AB - Inactivating STK11/LKB1 mutations are genomic drivers of primary resistance to immunotherapy in KRAS-mutated lung adenocarcinoma (LUAD), although the underlying mechanisms remain unelucidated. We find that LKB1 loss results in enhanced lactate production and secretion via the MCT4 transporter. Single-cell RNA profiling of murine models indicates that LKB1-deficient tumors have increased M2 macrophage polarization and hypofunctional T cells, effects that could be recapitulated by the addition of exogenous lactate and abrogated by MCT4 knockdown or therapeutic blockade of the lactate receptor GPR81 expressed on immune cells. Furthermore, MCT4 knockout reverses the resistance to PD-1 blockade induced by LKB1 loss in syngeneic murine models. Finally, tumors from STK11/LKB1 mutant LUAD patients demonstrate a similar phenotype of enhanced M2-macrophages polarization and hypofunctional T cells. These data provide evidence that lactate suppresses antitumor immunity and therapeutic targeting of this pathway is a promising strategy to reversing immunotherapy resistance in STK11/LKB1 mutant LUAD.

KW - immunotherapy resistance

KW - lactate

KW - LKB1

KW - lung adenocarcinoma

KW - macrophage polarization

KW - MCT4

KW - metabolism

KW - PD-1

KW - T cell activation

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U2 - 10.1016/j.ccell.2023.05.015

DO - 10.1016/j.ccell.2023.05.015

M3 - Article

C2 - 37327788

AN - SCOPUS:85164275662

SN - 1535-6108

VL - 41

SP - 1363-1380.e7

JO - Cancer cell

JF - Cancer cell

IS - 7

ER -

MCT4-dependent lactate secretion suppresses antitumor immunity in LKB1-deficient lung adenocarcinoma

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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