Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer

Michael J P Crowley; Bhavneet Bhinder; Geoffrey J Markowitz; Mitchell Martin; Akanksha Verma; Tito A Sandoval; Chang-Suk Chae; Shira Yomtoubian; Yang Hu; Sahil Chopra; Diamile A Tavarez; Paolo Giovanelli; Dingcheng Gao; Timothy E McGraw; Nasser K Altorki; Olivier Elemento; Juan R Cubillos-Ruiz; Vivek Mittal

doi:10.1038/s41467-022-35584-9

Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer

Nat Commun. 2023 Jan 9;14(1):120. doi: 10.1038/s41467-022-35584-9.

Authors

Michael J P Crowley^{1

2

3}, Bhavneet Bhinder^{4

5}, Geoffrey J Markowitz^{1

2

6}, Mitchell Martin^{1

2

3}, Akanksha Verma^{3

4

5

7}, Tito A Sandoval^{8

9}, Chang-Suk Chae^{8

9}, Shira Yomtoubian^{1

2

3

10}, Yang Hu^{4

5}, Sahil Chopra^{3

9

11}, Diamile A Tavarez^{1

2

12}, Paolo Giovanelli^{3

13}, Dingcheng Gao^{1

2

6}, Timothy E McGraw^{1

2

3

8

14}, Nasser K Altorki^{1

2

4

8}, Olivier Elemento^{4

5

8}, Juan R Cubillos-Ruiz^{15

16

17

18}, Vivek Mittal^{19

20

21

22

23

24}

Affiliations

¹ Department of Cardiothoracic Surgery, Weill Cornell Medicine, 525 East 68th street, New York, NY, 10065, USA.
² Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, 525 East 68th street, New York, NY, 10065, USA.
³ Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, 525 East 68th street, New York, NY, 10065, USA.
⁴ Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, 413 East 69th street, New York, NY, 10065, USA.
⁵ HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medicine, 525 East 68th street, New York, NY, 10065, USA.
⁶ Department of Cell and Developmental Biology, Weill Cornell Medicine, 525 East 68th street, New York, NYk, 10065, USA.
⁷ Volastra Therapeutics, New York, NY, 10027, USA.
⁸ Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, 413 East 69th street, New York, NY, 10065, USA.
⁹ Department of Obstetrics and Gynecology, Weill Cornell Medicine, 525 East 68th street, New York, NY, 10065, USA.
¹⁰ Salk Institute for Biological Studies, San Diego, CA, USA.
¹¹ Vertex Ventures HC, 345 California Avenue, Palo Alto, CA, 94306, USA.
¹² Regeneron Pharmaceuticals, 777 Old Saw Mill River Rd, Tarrytown, NY, 10591, USA.
¹³ Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine, 525 East 68th street, New York, NY, 10065, USA.
¹⁴ Department of Biochemistry, Weill Cornell Medicine, 525 East 68th street, New York, NY, 10065, USA.
¹⁵ Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, 525 East 68th street, New York, NY, 10065, USA. jur@med.cornell.edu.
¹⁶ Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, 413 East 69th street, New York, NY, 10065, USA. jur@med.cornell.edu.
¹⁷ Department of Obstetrics and Gynecology, Weill Cornell Medicine, 525 East 68th street, New York, NY, 10065, USA. jur@med.cornell.edu.
¹⁸ Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine, 525 East 68th street, New York, NY, 10065, USA. jur@med.cornell.edu.
¹⁹ Department of Cardiothoracic Surgery, Weill Cornell Medicine, 525 East 68th street, New York, NY, 10065, USA. vim2010@med.cornell.edu.
²⁰ Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, 525 East 68th street, New York, NY, 10065, USA. vim2010@med.cornell.edu.
²¹ Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, 525 East 68th street, New York, NY, 10065, USA. vim2010@med.cornell.edu.
²² Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, 413 East 69th street, New York, NY, 10065, USA. vim2010@med.cornell.edu.
²³ Department of Cell and Developmental Biology, Weill Cornell Medicine, 525 East 68th street, New York, NYk, 10065, USA. vim2010@med.cornell.edu.
²⁴ Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, 413 East 69th street, New York, NY, 10065, USA. vim2010@med.cornell.edu.

Abstract

IRE1α-XBP1 signaling is emerging as a central orchestrator of malignant progression and immunosuppression in various cancer types. Employing a computational XBP1s detection method applied to TCGA datasets, we demonstrate that expression of the XBP1s mRNA isoform predicts poor survival in non-small cell lung cancer (NSCLC) patients. Ablation of IRE1α in malignant cells delays tumor progression and extends survival in mouse models of NSCLC. This protective effect is accompanied by alterations in intratumoral immune cell subsets eliciting durable adaptive anti-cancer immunity. Mechanistically, cancer cell-intrinsic IRE1α activation sustains mPGES-1 expression, enabling production of the immunosuppressive lipid mediator prostaglandin E₂. Accordingly, restoring mPGES-1 expression in IRE1α^KO cancer cells rescues normal tumor progression. We have developed an IRE1α gene signature that predicts immune cell infiltration and overall survival in human NSCLC. Our study unveils an immunoregulatory role for cancer cell-intrinsic IRE1α activation and suggests that targeting this pathway may help enhance anti-tumor immunity in NSCLC.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Carcinoma, Non-Small-Cell Lung* / genetics
Endoribonucleases* / genetics
Endoribonucleases* / metabolism
Humans
Lung Neoplasms* / genetics
Mice
Protein Serine-Threonine Kinases* / genetics
Protein Serine-Threonine Kinases* / metabolism
Signal Transduction
X-Box Binding Protein 1 / genetics
X-Box Binding Protein 1 / metabolism

Substances

Endoribonucleases
Protein Serine-Threonine Kinases
X-Box Binding Protein 1
ERN1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding