Metabolomic adaptations and correlates of survival to immune checkpoint blockade

Haoxin Li; Kevin Bullock; Carino Gurjao; David Braun; Sachet A Shukla; Dominick Bossé; Aly-Khan A Lalani; Shuba Gopal; Chelsea Jin; Christine Horak; Megan Wind-Rotolo; Sabina Signoretti; David F McDermott; Gordon J Freeman; Eliezer M Van Allen; Stuart L Schreiber; F Stephen Hodi; William R Sellers; Levi A Garraway; Clary B Clish; Toni K Choueiri; Marios Giannakis

doi:10.1038/s41467-019-12361-9

Metabolomic adaptations and correlates of survival to immune checkpoint blockade

Nat Commun. 2019 Sep 25;10(1):4346. doi: 10.1038/s41467-019-12361-9.

Authors

Haoxin Li^{1

2

3}, Kevin Bullock², Carino Gurjao^{1

2}, David Braun¹, Sachet A Shukla¹, Dominick Bossé¹, Aly-Khan A Lalani¹, Shuba Gopal², Chelsea Jin⁴, Christine Horak⁴, Megan Wind-Rotolo⁴, Sabina Signoretti¹, David F McDermott⁵, Gordon J Freeman¹, Eliezer M Van Allen^{1

2

6}, Stuart L Schreiber^{2

3}, F Stephen Hodi^{1

6}, William R Sellers^{1

2}, Levi A Garraway^{1

2

6}, Clary B Clish², Toni K Choueiri^{7

8}, Marios Giannakis^{9

10

11}

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
² Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
³ Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, 02138, USA.
⁴ Bristol-Myers Squibb, Princeton, NJ, 08540, USA.
⁵ Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
⁶ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. [email protected].
⁸ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. [email protected].
⁹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. [email protected].
¹⁰ Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. [email protected].
¹¹ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. [email protected].

Abstract

Despite remarkable success of immune checkpoint inhibitors, the majority of cancer patients have yet to receive durable benefits. Here, in order to investigate the metabolic alterations in response to immune checkpoint blockade, we comprehensively profile serum metabolites in advanced melanoma and renal cell carcinoma patients treated with nivolumab, an antibody against programmed cell death protein 1 (PD1). We identify serum kynurenine/tryptophan ratio increases as an adaptive resistance mechanism associated with worse overall survival. This advocates for patient stratification and metabolic monitoring in immunotherapy clinical trials including those combining PD1 blockade with indoleamine 2,3-dioxygenase/tryptophan 2,3-dioxygenase (IDO/TDO) inhibitors.

Publication types

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

MeSH terms

Adaptation, Physiological / drug effects
Aged
Antineoplastic Agents / therapeutic use
Carcinoma, Renal Cell / blood
Carcinoma, Renal Cell / drug therapy*
Carcinoma, Renal Cell / metabolism
Clinical Trials as Topic
Everolimus / therapeutic use*
Female
Humans
Kaplan-Meier Estimate
Kidney Neoplasms / blood
Kidney Neoplasms / drug therapy*
Kidney Neoplasms / metabolism
Kynurenine / blood
Male
Melanoma / blood
Melanoma / drug therapy*
Melanoma / metabolism
Metabolomics*
Middle Aged
Nivolumab / therapeutic use*
Programmed Cell Death 1 Receptor / antagonists & inhibitors
Programmed Cell Death 1 Receptor / metabolism
Treatment Outcome
Tryptophan / blood

Substances

Antineoplastic Agents
PDCD1 protein, human
Programmed Cell Death 1 Receptor
Nivolumab
Kynurenine
Tryptophan
Everolimus

Abstract

Publication types

MeSH terms

Substances

Grants and funding