Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints

Koyama, Shohei; Akbay, Esra A.; Li, Yvonne Y.; Herter-Sprie, Grit S.; Buczkowski, Kevin A.; Richards, William G.; Gandhi, Leena; Redig, Amanda J.; Rodig, Scott J.; Asahina, Hajime; Jones, Robert E.; Kulkarni, Meghana; Kuraguchi, Mari; Palakurthi, Sangeetha; Fecci, Peter E.; Johnson, Bruce E.; Jänne, Pasi A.; Engelman, Jeffrey A.; Gangadharan, Sidhu P.; Costa, Daniel B.; Freeman, Gordon J.; Bueno, Raphael; Hodi, F. Stephen; Dranoff, Glenn; Wong, Kwok-Kin; Hammerman, Peter S.

doi:10.1038/ncomms10501

Cited by 1,237 publications

(1,029 citation statements)

References 39 publications

Supporting

Mentioning

929

Contrasting

Unclassified

Order By: Relevance

“…It is quite possible that targeting only 1 inhibitory receptor will be insufficient to release the inhibition on NK cells in all tumors. Other checkpoint receptors may be dynamically upregulated in an adaptive fashion similar to T cell immune checkpoint adaptive resistance recently observed in lung adenocarcinoma (74). Therefore, targeting multiple receptors on the NK cell population may be particularly useful in head and neck cancer.…”

Section: Discussionmentioning

confidence: 90%

The head and neck cancer immune landscape and its immunotherapeutic implications

Mandal¹,

Şenbabaoğlu

Desrichard³

et al. 2016

JCI Insight

612

613

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 90%

The head and neck cancer immune landscape and its immunotherapeutic implications

Mandal¹,

Şenbabaoğlu

Desrichard³

et al. 2016

JCI Insight

612

613

View full text Add to dashboard Cite

“…For instance, a recent preclinical study found T cells exploiting T-cell immunoglobulin mucin-3 (TIM3) to drive lung cancer growth despite anti-PD1 therapy. 42 Thus, future studies will have to concentrate on delineating such alternative GBM-associated immune checkpoints to design more tumor-specific ICIs.…”

Section: Discussionmentioning

confidence: 99%

Preclinical efficacy of immune-checkpoint monotherapy does not recapitulate corresponding biomarkers-based clinical predictions in glioblastoma

et al. 2017

View full text Add to dashboard Cite

Glioblastoma (GBM) is resistant to most multimodal therapies. Clinical success of immune-checkpoint inhibitors (ICIs) has spurred interest in applying ICIs targeting CTLA4, PD1 or IDO1 against GBM. This amplifies the need to ascertain GBM's intrinsic susceptibility (or resistance) toward these ICIs, through clinical biomarkers that may also "guide and prioritize" preclinical testing. Here, we interrogated the TCGA and/or REMBRANDT human patient-cohorts to predict GBM's predisposition toward ICIs. We exploited various broad clinical biomarkers, including mutational or predicted-neoantigen burden, pre-existing or basal levels of tumor-infiltrating T lymphocytes (TILs), differential expression of immune-checkpoints within the tumor and their correlation with particular TILs/Treg-associated functional signature and prognostic impact of differential immune-checkpoint expression. Based on these analyses, we found that predictive biomarkers of ICI responsiveness exhibited inconsistent patterns in GBM patients, i.e., they either predicted ICI resistance (as compared with typical ICI-responsive cancer-types like melanoma, lung cancer or bladder cancer) or susceptibility to therapeutic targeting of CTLA4 or IDO1. On the other hand, our comprehensive literature meta-analysis and preclinical testing of ICIs using an orthotopic GL261-glioma mice model, indicated significant antitumor properties of anti-PD1 antibody, whereas blockade of IDO1 or CTLA4 either failed or provided very marginal advantage. These trends raise the need to better assess the applicability of ICIs and associated biomarkers for GBM.

show abstract

“…25 Therefore, this study examines the efficacy and mechanism of dual anti-PD-1 and anti-TIGIT checkpoint blockade in a murine glioma model. We hypothesized that combination therapy leads to a significant increase in survival via modulations of both the T cell and myeloid compartments of the immune system.…”

Section: Introductionmentioning

confidence: 99%

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

et al. 2018

View full text Add to dashboard Cite

The use of inhibitory checkpoint blockade in the management of glioblastoma has been studied in both preclinical and clinical settings. TIGIT is a novel checkpoint inhibitor recently discovered to play a role in cancer immunity. In this study, we sought to determine the effect of anti-PD-1 and anti-TIGIT combination therapy on survival in a murine glioblastoma (GBM) model, and to elucidate the underlying immune mechanisms. Using mice with intracranial GL261-luc+ tumors, we found that TIGIT expression was upregulated on CD8+ and regulatory T cells (Tregs) in the brain compared to draining cervical lymph nodes (CLN) and spleen. We then demonstrated that treatment using anti-PD-1 and anti-TIGIT dual therapy significantly improved survival compared to control and monotherapy groups. The therapeutic effect was correlated with both increased effector T cell function and downregulation of suppressive Tregs and tumor-infiltrating dendritic cells (TIDCs). Clinically, TIGIT expression on tumor-infiltrating lymphocytes was shown to be elevated in patient GBM samples, suggesting that the TIGIT pathway may be a valuable therapeutic target. Expression of the TIGIT ligand, PVR, further portended a poor survival outcome in patients with low-grade glioma. We conclude that anti-TIGIT is an effective treatment strategy against murine GBM when used in combination with anti-PD-1, improving overall survival via modifications of both the T cell and myeloid compartments. Given evidence of PVR expression on human GBM cells, TIGIT presents as a promising immune therapeutic target in the management of these patients.

show abstract

Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints

Cited by 1,237 publications

References 39 publications

The head and neck cancer immune landscape and its immunotherapeutic implications

The head and neck cancer immune landscape and its immunotherapeutic implications

Preclinical efficacy of immune-checkpoint monotherapy does not recapitulate corresponding biomarkers-based clinical predictions in glioblastoma

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

Contact Info

Product

Resources

About