RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: Therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors

Sherene Loi, Sathana Dushyanthen, Paul A. Beavis, Roberto Salgado, Carsten Denkert, Peter Savas, Susan Combs, David L. Rimm, Jennifer M. Giltnane, Monica V. Estrada, Violeta Sánchez, Melinda E. Sanders, Rebecca S. Cook, Mark A. Pilkinton, Simon A. Mallal, Kai Wang, Vincent A. Miller, Phil J. Stephens, Roman Yelensky, Franco D. DoimiHenry Gómez, Sergey V. Ryzhov, Phillip K. Darcy, Carlos L. Arteaga, Justin M. Balko

Research output: Contribution to journalArticle

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Abstract

Purpose: Tumor-infiltrating lymphocytes (TIL) in the residual disease (RD) of triple-negative breast cancers (TNBC) after neoadjuvant chemotherapy (NAC) are associated with improved survival, but insight into tumor cell-autonomous molecular pathways affecting these features are lacking. Experimental Design: We analyzed TILs in the RD of clinically and molecularly characterized TNBCs after NAC and explored therapeutic strategies targeting combinations of MEK inhibitors with PD-1/PD-L1-targeted immunotherapy in mouse models of breast cancer. Results: Presence of TILs in the RD was significantly associated with improved prognosis. Genetic or transcriptomic alterations in Ras-MAPK signaling were significantly correlated with lower TILs. MEK inhibition upregulated cell surface MHC expression and PD-L1 in TNBC cells both in vivo and in vitro. Moreover, combined MEK and PD-L1/PD-1 inhibition enhanced antitumor immune responses in mouse models of breast cancer. Conclusions: These data suggest the possibility that Ras-MAPK pathway activation promotes immune-evasion in TNBC, and support clinical trials combining MEK- and PDL1-targeted therapies. Furthermore, Ras/MAPK activation andMHC expression may be predictive biomarkers of response to immune checkpoint inhibitors. Clin Cancer Res; 22(6); 1499-509.

Original languageEnglish (US)
Pages (from-to)1499-1509
Number of pages11
JournalClinical Cancer Research
Volume22
Issue number6
DOIs
StatePublished - Mar 15 2016

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Triple Negative Breast Neoplasms
Tumor-Infiltrating Lymphocytes
Mitogen-Activated Protein Kinase Kinases
Breast Neoplasms
Immune Evasion
Drug Therapy
Therapeutics
Immunotherapy
Neoplasms
Research Design
Biomarkers
Clinical Trials

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer : Therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors. / Loi, Sherene; Dushyanthen, Sathana; Beavis, Paul A.; Salgado, Roberto; Denkert, Carsten; Savas, Peter; Combs, Susan; Rimm, David L.; Giltnane, Jennifer M.; Estrada, Monica V.; Sánchez, Violeta; Sanders, Melinda E.; Cook, Rebecca S.; Pilkinton, Mark A.; Mallal, Simon A.; Wang, Kai; Miller, Vincent A.; Stephens, Phil J.; Yelensky, Roman; Doimi, Franco D.; Gómez, Henry; Ryzhov, Sergey V.; Darcy, Phillip K.; Arteaga, Carlos L.; Balko, Justin M.

In: Clinical Cancer Research, Vol. 22, No. 6, 15.03.2016, p. 1499-1509.

Research output: Contribution to journalArticle

Loi, S, Dushyanthen, S, Beavis, PA, Salgado, R, Denkert, C, Savas, P, Combs, S, Rimm, DL, Giltnane, JM, Estrada, MV, Sánchez, V, Sanders, ME, Cook, RS, Pilkinton, MA, Mallal, SA, Wang, K, Miller, VA, Stephens, PJ, Yelensky, R, Doimi, FD, Gómez, H, Ryzhov, SV, Darcy, PK, Arteaga, CL & Balko, JM 2016, 'RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: Therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors', Clinical Cancer Research, vol. 22, no. 6, pp. 1499-1509. https://doi.org/10.1158/1078-0432.CCR-15-1125
Loi, Sherene ; Dushyanthen, Sathana ; Beavis, Paul A. ; Salgado, Roberto ; Denkert, Carsten ; Savas, Peter ; Combs, Susan ; Rimm, David L. ; Giltnane, Jennifer M. ; Estrada, Monica V. ; Sánchez, Violeta ; Sanders, Melinda E. ; Cook, Rebecca S. ; Pilkinton, Mark A. ; Mallal, Simon A. ; Wang, Kai ; Miller, Vincent A. ; Stephens, Phil J. ; Yelensky, Roman ; Doimi, Franco D. ; Gómez, Henry ; Ryzhov, Sergey V. ; Darcy, Phillip K. ; Arteaga, Carlos L. ; Balko, Justin M. / RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer : Therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 6. pp. 1499-1509.
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abstract = "Purpose: Tumor-infiltrating lymphocytes (TIL) in the residual disease (RD) of triple-negative breast cancers (TNBC) after neoadjuvant chemotherapy (NAC) are associated with improved survival, but insight into tumor cell-autonomous molecular pathways affecting these features are lacking. Experimental Design: We analyzed TILs in the RD of clinically and molecularly characterized TNBCs after NAC and explored therapeutic strategies targeting combinations of MEK inhibitors with PD-1/PD-L1-targeted immunotherapy in mouse models of breast cancer. Results: Presence of TILs in the RD was significantly associated with improved prognosis. Genetic or transcriptomic alterations in Ras-MAPK signaling were significantly correlated with lower TILs. MEK inhibition upregulated cell surface MHC expression and PD-L1 in TNBC cells both in vivo and in vitro. Moreover, combined MEK and PD-L1/PD-1 inhibition enhanced antitumor immune responses in mouse models of breast cancer. Conclusions: These data suggest the possibility that Ras-MAPK pathway activation promotes immune-evasion in TNBC, and support clinical trials combining MEK- and PDL1-targeted therapies. Furthermore, Ras/MAPK activation andMHC expression may be predictive biomarkers of response to immune checkpoint inhibitors. Clin Cancer Res; 22(6); 1499-509.",
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T1 - RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer

T2 - Therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors

AU - Loi, Sherene

AU - Dushyanthen, Sathana

AU - Beavis, Paul A.

AU - Salgado, Roberto

AU - Denkert, Carsten

AU - Savas, Peter

AU - Combs, Susan

AU - Rimm, David L.

AU - Giltnane, Jennifer M.

AU - Estrada, Monica V.

AU - Sánchez, Violeta

AU - Sanders, Melinda E.

AU - Cook, Rebecca S.

AU - Pilkinton, Mark A.

AU - Mallal, Simon A.

AU - Wang, Kai

AU - Miller, Vincent A.

AU - Stephens, Phil J.

AU - Yelensky, Roman

AU - Doimi, Franco D.

AU - Gómez, Henry

AU - Ryzhov, Sergey V.

AU - Darcy, Phillip K.

AU - Arteaga, Carlos L.

AU - Balko, Justin M.

PY - 2016/3/15

Y1 - 2016/3/15

N2 - Purpose: Tumor-infiltrating lymphocytes (TIL) in the residual disease (RD) of triple-negative breast cancers (TNBC) after neoadjuvant chemotherapy (NAC) are associated with improved survival, but insight into tumor cell-autonomous molecular pathways affecting these features are lacking. Experimental Design: We analyzed TILs in the RD of clinically and molecularly characterized TNBCs after NAC and explored therapeutic strategies targeting combinations of MEK inhibitors with PD-1/PD-L1-targeted immunotherapy in mouse models of breast cancer. Results: Presence of TILs in the RD was significantly associated with improved prognosis. Genetic or transcriptomic alterations in Ras-MAPK signaling were significantly correlated with lower TILs. MEK inhibition upregulated cell surface MHC expression and PD-L1 in TNBC cells both in vivo and in vitro. Moreover, combined MEK and PD-L1/PD-1 inhibition enhanced antitumor immune responses in mouse models of breast cancer. Conclusions: These data suggest the possibility that Ras-MAPK pathway activation promotes immune-evasion in TNBC, and support clinical trials combining MEK- and PDL1-targeted therapies. Furthermore, Ras/MAPK activation andMHC expression may be predictive biomarkers of response to immune checkpoint inhibitors. Clin Cancer Res; 22(6); 1499-509.

AB - Purpose: Tumor-infiltrating lymphocytes (TIL) in the residual disease (RD) of triple-negative breast cancers (TNBC) after neoadjuvant chemotherapy (NAC) are associated with improved survival, but insight into tumor cell-autonomous molecular pathways affecting these features are lacking. Experimental Design: We analyzed TILs in the RD of clinically and molecularly characterized TNBCs after NAC and explored therapeutic strategies targeting combinations of MEK inhibitors with PD-1/PD-L1-targeted immunotherapy in mouse models of breast cancer. Results: Presence of TILs in the RD was significantly associated with improved prognosis. Genetic or transcriptomic alterations in Ras-MAPK signaling were significantly correlated with lower TILs. MEK inhibition upregulated cell surface MHC expression and PD-L1 in TNBC cells both in vivo and in vitro. Moreover, combined MEK and PD-L1/PD-1 inhibition enhanced antitumor immune responses in mouse models of breast cancer. Conclusions: These data suggest the possibility that Ras-MAPK pathway activation promotes immune-evasion in TNBC, and support clinical trials combining MEK- and PDL1-targeted therapies. Furthermore, Ras/MAPK activation andMHC expression may be predictive biomarkers of response to immune checkpoint inhibitors. Clin Cancer Res; 22(6); 1499-509.

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