HLA export by melanoma cells decoys cytotoxic T cells to promote immune evasion

Yoav Chemla; Orit Itzhaki; Stav Melamed; Chen Weller; Yuval Sade; Paulee Manich; Keren Reshef; Nicolas Xenidis; Avishai Maliah; Gilad Levy; Roma Parikh; Osnat Bartok; Opal Levy; Itay Tal; Gal Aziel; Abraham Nissani; Sharon Yunger; Daniela Likonen; Vitaly Kliminsky; Tamar Golan; Coralie Capron; Valentina Ace; Ronen Levy; Diana Rasoulouniriana; Zohar Eyal; Yuval Barzilay; Roi Balaban; Aseel Khateeb; Rami Khosravi; Amir Grau; Tamar Ziv; Polina Greenberg; Dvir Netanely; Hananya Vaknin; Xunwei Wu; Yael Amitay; Ronen Brenner; Julia María Martínez Gómez; Dov Hershkovitz; Tal Yardeni; Valentina Zemser-Werner; Oren Kobiler; Yael Friedmann; David Bassan; Ron Shamir; Lea Eisenbach; Nadine Santana-Magal; Michael Milyavsky; Galit Eisenberg; Leeat Keren; Merav Cohen; Dvir Gur; Boaz Barak; Michal Lotem; David Sprinzak; Shoshana Greenberger; David Fisher; Michal J. Besser; Mehdi Khaled; Pierre Close; Ronnie Shapira; Sebastien Apcher; Asaf Madi; Mitchell P. Levesque; Francessca Rapino; Yaron Carmi; Shivang Parikh; Yardena Samuels; Carmit Levy

doi:10.1016/j.cell.2025.11.020

HLA export by melanoma cells decoys cytotoxic T cells to promote immune evasion

Yoav Chemla
, Orit Itzhaki
, Stav Melamed
, Chen Weller
, Yuval Sade
, Paulee Manich
, Keren Reshef
, Nicolas Xenidis
, Avishai Maliah
, Gilad Levy
, Roma Parikh
, Osnat Bartok
, Opal Levy
, Itay Tal
, Gal Aziel
, Abraham Nissani
, Sharon Yunger
, Daniela Likonen
, Vitaly Kliminsky
, Tamar Golan

Coralie Capron, Valentina Ace, Ronen Levy, Diana Rasoulouniriana, Zohar Eyal, Yuval Barzilay, Roi Balaban, Aseel Khateeb, Rami Khosravi, Amir Grau, Tamar Ziv, Polina Greenberg, Dvir Netanely, Hananya Vaknin, Xunwei Wu, Yael Amitay, Ronen Brenner, Julia María Martínez Gómez, Dov Hershkovitz, Tal Yardeni, Valentina Zemser-Werner, Oren Kobiler, Yael Friedmann, David Bassan, Ron Shamir, Lea Eisenbach, Nadine Santana-Magal, Michael Milyavsky, Galit Eisenberg, Leeat Keren, Merav Cohen, Dvir Gur, Boaz Barak, Michal Lotem, David Sprinzak, Shoshana Greenberger, David Fisher, Michal J. Besser, Mehdi Khaled^*, Pierre Close^*, Ronnie Shapira^*, Sebastien Apcher^*, Asaf Madi^*, Mitchell P. Levesque^*, Francessca Rapino^*, Yaron Carmi^*, Shivang Parikh^*, Yardena Samuels^*, Carmit Levy^*

^*Corresponding author for this work

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

Abstract

While melanoma cells often express a high burden of mutated proteins, the infiltration of reactive T cells rarely results in tumor-eradicating immunity. We discovered that large extracellular vesicles, known as melanosomes, secreted by melanoma cells are decorated with major histocompatibility complex (MHC) molecules that stimulate CD8⁺ T cells through their T cell receptor (TCR), causing T cell dysfunction and apoptosis. Immunopeptidomic and T cell receptor sequencing (TCR-seq) analyses revealed that these melanosomes carry MHC-bound tumor-associated antigens with higher affinity and immunogenicity, which compete with their tumor cell of origin for direct TCR-MHC interactions. Analysis of biopsies from melanoma patients confirmed that melanosomes trap infiltrating lymphocytes, induce partial activation, and decrease CD8⁺ T cell cytotoxicity. Inhibition of melanosome secretion in vivo significantly reduced tumor immune evasion. These findings suggest that MHC export protects melanoma from the cytotoxic effects of T cells. Our study highlights a novel immune evasion mechanism and proposes a therapeutic avenue to enhance tumor immunity.

Original language	English
Pages (from-to)	233-251.e29
Journal	Cell
Volume	189
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2025.11.020
Publication status	Published Online - 15 Dec 2025

Funding

C.L. acknoledges that this work was funded by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program European Union. Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or the ERCEA. Neither the European Union nor the granting authority can be held responsible for them (C.L., grant agreement no. 726225). C.L. acknowledges the Tel Aviv University Gray Medical School core facility, Medina and Elisha with endless gratitude, and Yuval and Omer for exponential joy. D.F. acknowledges the NIH grants NCI P01 CA163222 and NIAMS R01 AR043369-27 and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. A.M. acknowledges the Mantoux Bioinformatics Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine and specifically Dr. Avital Sarusi Portuguez.

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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10.1016/j.cell.2025.11.020Licence: CC BY

Cite this

Chemla, Y., Itzhaki, O., Melamed, S., Weller, C., Sade, Y., Manich, P., Reshef, K., Xenidis, N., Maliah, A., Levy, G., Parikh, R., Bartok, O., Levy, O., Tal, I., Aziel, G., Nissani, A., Yunger, S., Likonen, D., Kliminsky, V., ... Levy, C. (2025). HLA export by melanoma cells decoys cytotoxic T cells to promote immune evasion. Cell, 189(1), 233-251.e29. Advance online publication. https://doi.org/10.1016/j.cell.2025.11.020

@article{bec29b0fa0d04ffdac12dd1d5f2f2f1a,

title = "HLA export by melanoma cells decoys cytotoxic T cells to promote immune evasion",

abstract = "While melanoma cells often express a high burden of mutated proteins, the infiltration of reactive T cells rarely results in tumor-eradicating immunity. We discovered that large extracellular vesicles, known as melanosomes, secreted by melanoma cells are decorated with major histocompatibility complex (MHC) molecules that stimulate CD8+ T cells through their T cell receptor (TCR), causing T cell dysfunction and apoptosis. Immunopeptidomic and T cell receptor sequencing (TCR-seq) analyses revealed that these melanosomes carry MHC-bound tumor-associated antigens with higher affinity and immunogenicity, which compete with their tumor cell of origin for direct TCR-MHC interactions. Analysis of biopsies from melanoma patients confirmed that melanosomes trap infiltrating lymphocytes, induce partial activation, and decrease CD8+ T cell cytotoxicity. Inhibition of melanosome secretion in vivo significantly reduced tumor immune evasion. These findings suggest that MHC export protects melanoma from the cytotoxic effects of T cells. Our study highlights a novel immune evasion mechanism and proposes a therapeutic avenue to enhance tumor immunity.",

author = "Yoav Chemla and Orit Itzhaki and Stav Melamed and Chen Weller and Yuval Sade and Paulee Manich and Keren Reshef and Nicolas Xenidis and Avishai Maliah and Gilad Levy and Roma Parikh and Osnat Bartok and Opal Levy and Itay Tal and Gal Aziel and Abraham Nissani and Sharon Yunger and Daniela Likonen and Vitaly Kliminsky and Tamar Golan and Coralie Capron and Valentina Ace and Ronen Levy and Diana Rasoulouniriana and Zohar Eyal and Yuval Barzilay and Roi Balaban and Aseel Khateeb and Rami Khosravi and Amir Grau and Tamar Ziv and Polina Greenberg and Dvir Netanely and Hananya Vaknin and Xunwei Wu and Yael Amitay and Ronen Brenner and \{Mart{\'i}nez G{\'o}mez\}, \{Julia Mar{\'i}a\} and Dov Hershkovitz and Tal Yardeni and Valentina Zemser-Werner and Oren Kobiler and Yael Friedmann and David Bassan and Ron Shamir and Lea Eisenbach and Nadine Santana-Magal and Michael Milyavsky and Galit Eisenberg and Leeat Keren and Merav Cohen and Dvir Gur and Boaz Barak and Michal Lotem and David Sprinzak and Shoshana Greenberger and David Fisher and Besser, \{Michal J.\} and Mehdi Khaled and Pierre Close and Ronnie Shapira and Sebastien Apcher and Asaf Madi and Levesque, \{Mitchell P.\} and Francessca Rapino and Yaron Carmi and Shivang Parikh and Yardena Samuels and Carmit Levy",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors.",

year = "2025",

month = dec,

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doi = "10.1016/j.cell.2025.11.020",

language = "English",

volume = "189",

pages = "233--251.e29",

journal = "Cell",

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Chemla, Y, Itzhaki, O, Melamed, S, Weller, C, Sade, Y, Manich, P, Reshef, K, Xenidis, N, Maliah, A, Levy, G, Parikh, R, Bartok, O, Levy, O, Tal, I, Aziel, G, Nissani, A, Yunger, S, Likonen, D, Kliminsky, V, Golan, T, Capron, C, Ace, V, Levy, R, Rasoulouniriana, D, Eyal, Z , Barzilay, Y, Balaban, R, Khateeb, A, Khosravi, R, Grau, A, Ziv, T, Greenberg, P, Netanely, D, Vaknin, H, Wu, X, Amitay, Y, Brenner, R, Martínez Gómez, JM, Hershkovitz, D, Yardeni, T, Zemser-Werner, V, Kobiler, O, Friedmann, Y, Bassan, D, Shamir, R, Eisenbach, L, Santana-Magal, N, Milyavsky, M, Eisenberg, G, Keren, L, Cohen, M, Gur, D, Barak, B, Lotem, M, Sprinzak, D, Greenberger, S, Fisher, D, Besser, MJ, Khaled, M, Close, P, Shapira, R, Apcher, S, Madi, A, Levesque, MP, Rapino, F, Carmi, Y, Parikh, S, Samuels, Y & Levy, C 2025, 'HLA export by melanoma cells decoys cytotoxic T cells to promote immune evasion', Cell, vol. 189, no. 1, pp. 233-251.e29. https://doi.org/10.1016/j.cell.2025.11.020

TY - JOUR

T1 - HLA export by melanoma cells decoys cytotoxic T cells to promote immune evasion

AU - Chemla, Yoav

AU - Itzhaki, Orit

AU - Melamed, Stav

AU - Weller, Chen

AU - Sade, Yuval

AU - Manich, Paulee

AU - Reshef, Keren

AU - Xenidis, Nicolas

AU - Maliah, Avishai

AU - Levy, Gilad

AU - Parikh, Roma

AU - Bartok, Osnat

AU - Levy, Opal

AU - Tal, Itay

AU - Aziel, Gal

AU - Nissani, Abraham

AU - Yunger, Sharon

AU - Likonen, Daniela

AU - Kliminsky, Vitaly

AU - Golan, Tamar

AU - Capron, Coralie

AU - Ace, Valentina

AU - Levy, Ronen

AU - Rasoulouniriana, Diana

AU - Eyal, Zohar

AU - Barzilay, Yuval

AU - Balaban, Roi

AU - Khateeb, Aseel

AU - Khosravi, Rami

AU - Grau, Amir

AU - Ziv, Tamar

AU - Greenberg, Polina

AU - Netanely, Dvir

AU - Vaknin, Hananya

AU - Wu, Xunwei

AU - Amitay, Yael

AU - Brenner, Ronen

AU - Martínez Gómez, Julia María

AU - Hershkovitz, Dov

AU - Yardeni, Tal

AU - Zemser-Werner, Valentina

AU - Kobiler, Oren

AU - Friedmann, Yael

AU - Bassan, David

AU - Shamir, Ron

AU - Eisenbach, Lea

AU - Santana-Magal, Nadine

AU - Milyavsky, Michael

AU - Eisenberg, Galit

AU - Keren, Leeat

AU - Cohen, Merav

AU - Gur, Dvir

AU - Barak, Boaz

AU - Lotem, Michal

AU - Sprinzak, David

AU - Greenberger, Shoshana

AU - Fisher, David

AU - Besser, Michal J.

AU - Khaled, Mehdi

AU - Close, Pierre

AU - Shapira, Ronnie

AU - Apcher, Sebastien

AU - Madi, Asaf

AU - Levesque, Mitchell P.

AU - Rapino, Francessca

AU - Carmi, Yaron

AU - Parikh, Shivang

AU - Samuels, Yardena

AU - Levy, Carmit

PY - 2025/12/15

Y1 - 2025/12/15

N2 - While melanoma cells often express a high burden of mutated proteins, the infiltration of reactive T cells rarely results in tumor-eradicating immunity. We discovered that large extracellular vesicles, known as melanosomes, secreted by melanoma cells are decorated with major histocompatibility complex (MHC) molecules that stimulate CD8+ T cells through their T cell receptor (TCR), causing T cell dysfunction and apoptosis. Immunopeptidomic and T cell receptor sequencing (TCR-seq) analyses revealed that these melanosomes carry MHC-bound tumor-associated antigens with higher affinity and immunogenicity, which compete with their tumor cell of origin for direct TCR-MHC interactions. Analysis of biopsies from melanoma patients confirmed that melanosomes trap infiltrating lymphocytes, induce partial activation, and decrease CD8+ T cell cytotoxicity. Inhibition of melanosome secretion in vivo significantly reduced tumor immune evasion. These findings suggest that MHC export protects melanoma from the cytotoxic effects of T cells. Our study highlights a novel immune evasion mechanism and proposes a therapeutic avenue to enhance tumor immunity.

AB - While melanoma cells often express a high burden of mutated proteins, the infiltration of reactive T cells rarely results in tumor-eradicating immunity. We discovered that large extracellular vesicles, known as melanosomes, secreted by melanoma cells are decorated with major histocompatibility complex (MHC) molecules that stimulate CD8+ T cells through their T cell receptor (TCR), causing T cell dysfunction and apoptosis. Immunopeptidomic and T cell receptor sequencing (TCR-seq) analyses revealed that these melanosomes carry MHC-bound tumor-associated antigens with higher affinity and immunogenicity, which compete with their tumor cell of origin for direct TCR-MHC interactions. Analysis of biopsies from melanoma patients confirmed that melanosomes trap infiltrating lymphocytes, induce partial activation, and decrease CD8+ T cell cytotoxicity. Inhibition of melanosome secretion in vivo significantly reduced tumor immune evasion. These findings suggest that MHC export protects melanoma from the cytotoxic effects of T cells. Our study highlights a novel immune evasion mechanism and proposes a therapeutic avenue to enhance tumor immunity.

UR - https://www.scopus.com/pages/publications/105025106060

U2 - 10.1016/j.cell.2025.11.020

DO - 10.1016/j.cell.2025.11.020

M3 - Article

C2 - 41401806

AN - SCOPUS:105025106060

SN - 0092-8674

VL - 189

SP - 233-251.e29

JO - Cell

JF - Cell

IS - 1

ER -

HLA export by melanoma cells decoys cytotoxic T cells to promote immune evasion

Abstract

Funding

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