Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma

Catherine S. Grasso; Jennifer Tsoi; Mykola Onyshchenko; Gabriel Abril-Rodriguez; Petra Ross-Macdonald; Megan Wind-Rotolo; Ameya Champhekar; Egmidio Medina; Davis Y. Torrejon; Daniel Sanghoon Shin; Phuong Tran; Yeon Joo Kim; Cristina Puig-Saus; Katie Campbell; Agustin Vega-Crespo; Michael Quist; Christophe Martignier; Jason J. Luke; Jedd D. Wolchok; Douglas B. Johnson; Bartosz Chmielowski; F. Stephen Hodi; Shailender Bhatia; William Sharfman; Walter J. Urba; Craig L. Slingluff; Adi Diab; John B.A.G. Haanen; Salvador Martin Algarra; Drew M. Pardoll; Valsamo Anagnostou; Suzanne L. Topalian; Victor E. Velculescu; Daniel E. Speiser; Anusha Kalbasi; Antoni Ribas

doi:10.1016/j.ccell.2020.08.005

Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma

Catherine S. Grasso, Jennifer Tsoi, Mykola Onyshchenko, Gabriel Abril-Rodriguez, Petra Ross-Macdonald, Megan Wind-Rotolo, Ameya Champhekar, Egmidio Medina, Davis Y. Torrejon, Daniel Sanghoon Shin, Phuong Tran, Yeon Joo Kim, Cristina Puig-Saus, Katie Campbell, Agustin Vega-Crespo, Michael Quist, Christophe Martignier, Jason J. Luke, Jedd D. Wolchok, Douglas B. JohnsonBartosz Chmielowski, F. Stephen Hodi, Shailender Bhatia, William Sharfman, Walter J. Urba, Craig L. Slingluff, Adi Diab, John B.A.G. Haanen, Salvador Martin Algarra, Drew M. Pardoll, Valsamo Anagnostou, Suzanne L. Topalian, Victor E. Velculescu, Daniel E. Speiser, Anusha Kalbasi, Antoni Ribas

School of Medicine

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

15 Scopus citations

Abstract

We analyze the transcriptome of baseline and on-therapy tumor biopsies from 101 patients with advanced melanoma treated with nivolumab (anti-PD-1) alone or combined with ipilimumab (anti-CTLA-4). We find that T cell infiltration and interferon-γ (IFN-γ) signaling signatures correspond most highly with clinical response to therapy, with a reciprocal decrease in cell-cycle and WNT signaling pathways in responding biopsies. We model the interaction in 58 human cell lines, where IFN-γ in vitro exposure leads to a conserved transcriptome response unless cells have IFN-γ receptor alterations. This conserved IFN-γ transcriptome response in melanoma cells serves to amplify the antitumor immune response. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream IFN-γ signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy.

Original language	English (US)
Pages (from-to)	500-515.e3
Journal	Cancer cell
Volume	38
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2020.08.005
State	Published - Oct 12 2020

Keywords

RNA-seq
anti-CTLA-4
anti-PD-1
biopsies
clinical trial
immune checkpoint blockade
immune exclusion
interferon-γ
resistance
response
transcriptomics

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccell.2020.08.005

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Grasso, C. S., Tsoi, J., Onyshchenko, M., Abril-Rodriguez, G., Ross-Macdonald, P., Wind-Rotolo, M., Champhekar, A., Medina, E., Torrejon, D. Y., Shin, D. S., Tran, P., Kim, Y. J., Puig-Saus, C., Campbell, K., Vega-Crespo, A., Quist, M., Martignier, C., Luke, J. J., Wolchok, J. D., ... Ribas, A. (2020). Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma. Cancer cell, 38(4), 500-515.e3. https://doi.org/10.1016/j.ccell.2020.08.005

Grasso, CS, Tsoi, J, Onyshchenko, M, Abril-Rodriguez, G, Ross-Macdonald, P, Wind-Rotolo, M, Champhekar, A, Medina, E, Torrejon, DY, Shin, DS, Tran, P, Kim, YJ, Puig-Saus, C, Campbell, K, Vega-Crespo, A, Quist, M, Martignier, C, Luke, JJ, Wolchok, JD, Johnson, DB, Chmielowski, B, Hodi, FS, Bhatia, S, Sharfman, W, Urba, WJ, Slingluff, CL, Diab, A, Haanen, JBAG, Algarra, SM, Pardoll, DM , Anagnostou, V , Topalian, SL , Velculescu, VE, Speiser, DE, Kalbasi, A & Ribas, A 2020, 'Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma', Cancer cell, vol. 38, no. 4, pp. 500-515.e3. https://doi.org/10.1016/j.ccell.2020.08.005

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title = "Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma",

abstract = "We analyze the transcriptome of baseline and on-therapy tumor biopsies from 101 patients with advanced melanoma treated with nivolumab (anti-PD-1) alone or combined with ipilimumab (anti-CTLA-4). We find that T cell infiltration and interferon-γ (IFN-γ) signaling signatures correspond most highly with clinical response to therapy, with a reciprocal decrease in cell-cycle and WNT signaling pathways in responding biopsies. We model the interaction in 58 human cell lines, where IFN-γ in vitro exposure leads to a conserved transcriptome response unless cells have IFN-γ receptor alterations. This conserved IFN-γ transcriptome response in melanoma cells serves to amplify the antitumor immune response. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream IFN-γ signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy.",

keywords = "RNA-seq, anti-CTLA-4, anti-PD-1, biopsies, clinical trial, immune checkpoint blockade, immune exclusion, interferon-γ, resistance, response, transcriptomics",

author = "Grasso, {Catherine S.} and Jennifer Tsoi and Mykola Onyshchenko and Gabriel Abril-Rodriguez and Petra Ross-Macdonald and Megan Wind-Rotolo and Ameya Champhekar and Egmidio Medina and Torrejon, {Davis Y.} and Shin, {Daniel Sanghoon} and Phuong Tran and Kim, {Yeon Joo} and Cristina Puig-Saus and Katie Campbell and Agustin Vega-Crespo and Michael Quist and Christophe Martignier and Luke, {Jason J.} and Wolchok, {Jedd D.} and Johnson, {Douglas B.} and Bartosz Chmielowski and Hodi, {F. Stephen} and Shailender Bhatia and William Sharfman and Urba, {Walter J.} and Slingluff, {Craig L.} and Adi Diab and Haanen, {John B.A.G.} and Algarra, {Salvador Martin} and Pardoll, {Drew M.} and Valsamo Anagnostou and Topalian, {Suzanne L.} and Velculescu, {Victor E.} and Speiser, {Daniel E.} and Anusha Kalbasi and Antoni Ribas",

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doi = "10.1016/j.ccell.2020.08.005",

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T1 - Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma

AU - Grasso, Catherine S.

AU - Tsoi, Jennifer

AU - Onyshchenko, Mykola

AU - Abril-Rodriguez, Gabriel

AU - Ross-Macdonald, Petra

AU - Wind-Rotolo, Megan

AU - Champhekar, Ameya

AU - Medina, Egmidio

AU - Torrejon, Davis Y.

AU - Shin, Daniel Sanghoon

AU - Tran, Phuong

AU - Kim, Yeon Joo

AU - Puig-Saus, Cristina

AU - Campbell, Katie

AU - Vega-Crespo, Agustin

AU - Quist, Michael

AU - Martignier, Christophe

AU - Luke, Jason J.

AU - Wolchok, Jedd D.

AU - Johnson, Douglas B.

AU - Chmielowski, Bartosz

AU - Hodi, F. Stephen

AU - Bhatia, Shailender

AU - Sharfman, William

AU - Urba, Walter J.

AU - Slingluff, Craig L.

AU - Diab, Adi

AU - Haanen, John B.A.G.

AU - Algarra, Salvador Martin

AU - Pardoll, Drew M.

AU - Anagnostou, Valsamo

AU - Topalian, Suzanne L.

AU - Velculescu, Victor E.

AU - Speiser, Daniel E.

AU - Kalbasi, Anusha

AU - Ribas, Antoni

PY - 2020/10/12

Y1 - 2020/10/12

N2 - We analyze the transcriptome of baseline and on-therapy tumor biopsies from 101 patients with advanced melanoma treated with nivolumab (anti-PD-1) alone or combined with ipilimumab (anti-CTLA-4). We find that T cell infiltration and interferon-γ (IFN-γ) signaling signatures correspond most highly with clinical response to therapy, with a reciprocal decrease in cell-cycle and WNT signaling pathways in responding biopsies. We model the interaction in 58 human cell lines, where IFN-γ in vitro exposure leads to a conserved transcriptome response unless cells have IFN-γ receptor alterations. This conserved IFN-γ transcriptome response in melanoma cells serves to amplify the antitumor immune response. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream IFN-γ signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy.

AB - We analyze the transcriptome of baseline and on-therapy tumor biopsies from 101 patients with advanced melanoma treated with nivolumab (anti-PD-1) alone or combined with ipilimumab (anti-CTLA-4). We find that T cell infiltration and interferon-γ (IFN-γ) signaling signatures correspond most highly with clinical response to therapy, with a reciprocal decrease in cell-cycle and WNT signaling pathways in responding biopsies. We model the interaction in 58 human cell lines, where IFN-γ in vitro exposure leads to a conserved transcriptome response unless cells have IFN-γ receptor alterations. This conserved IFN-γ transcriptome response in melanoma cells serves to amplify the antitumor immune response. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream IFN-γ signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy.

KW - RNA-seq

KW - anti-CTLA-4

KW - anti-PD-1

KW - biopsies

KW - clinical trial

KW - immune checkpoint blockade

KW - immune exclusion

KW - interferon-γ

KW - resistance

KW - response

KW - transcriptomics

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UR - http://www.scopus.com/inward/citedby.url?scp=85092344130&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2020.08.005

DO - 10.1016/j.ccell.2020.08.005

M3 - Article

C2 - 32916126

AN - SCOPUS:85092344130

SN - 1535-6108

VL - 38

SP - 500-515.e3

JO - Cancer cell

JF - Cancer cell

IS - 4

ER -

Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma

Abstract

Keywords

ASJC Scopus subject areas

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