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Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens.

Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, Ivanova Y, Hundal J, Arthur CD, Krebber WJ, Mulder GE, Toebes M, Vesely MD, Lam SS, Korman AJ, Allison JP, Freeman GJ, Sharpe AH, Pearce EL, Schumacher TN, Aebersold R, Rammensee HG, Melief CJ, Mardis ER, Gillanders WE, Artyomov MN, Schreiber RD - Nature (2014)

Bottom Line: Yet, clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer-induced immunosuppression.Monoclonal-antibody-based therapies targeting CTLA-4 and/or PD-1 (checkpoint blockade) have yielded significant clinical benefits-including durable responses--to patients with different malignancies.These results reveal that tumour-specific mutant antigens are not only important targets of checkpoint blockade therapy, but they can also be used to develop personalized cancer-specific vaccines and to probe the mechanistic underpinnings of different checkpoint blockade treatments.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.

ABSTRACT
The immune system influences the fate of developing cancers by not only functioning as a tumour promoter that facilitates cellular transformation, promotes tumour growth and sculpts tumour cell immunogenicity, but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion. Yet, clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer-induced immunosuppression. In many individuals, immunosuppression is mediated by cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), two immunomodulatory receptors expressed on T cells. Monoclonal-antibody-based therapies targeting CTLA-4 and/or PD-1 (checkpoint blockade) have yielded significant clinical benefits-including durable responses--to patients with different malignancies. However, little is known about the identity of the tumour antigens that function as the targets of T cells activated by checkpoint blockade immunotherapy and whether these antigens can be used to generate vaccines that are highly tumour-specific. Here we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T-cell rejection antigens following anti-PD-1 and/or anti-CTLA-4 therapy of mice bearing progressively growing sarcomas, and we show that therapeutic synthetic long-peptide vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Although mutant tumour-antigen-specific T cells are present in progressively growing tumours, they are reactivated following treatment with anti-PD-1 and/or anti-CTLA-4 and display some overlapping but mostly treatment-specific transcriptional profiles, rendering them capable of mediating tumour rejection. These results reveal that tumour-specific mutant antigens are not only important targets of checkpoint blockade therapy, but they can also be used to develop personalized cancer-specific vaccines and to probe the mechanistic underpinnings of different checkpoint blockade treatments.

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mLama4 and mAlg8 stimulate CD8+ T cell lines generated against d42m1-T3 following αPD-1a, CD8+ T cell lines generated from splenocytes of individual d42m1-T3 tumour bearing mice that rejected their tumours after αPD-1 therapy were incubated with irradiated d42m1-T3 tumour cells (or F244 tumour cells) treated with blocking mAb specific for H-2Kb, and/or H-2Db and IFN-γ production quantitated. Data are presented as means ± s.e.m and are representative of two independent experiments. Samples were compared using an unpaired, two-tailed Student’s t test (***p<0.001). b, IFN-γ release by the CTL 74 T cell line following co-culture with naïve irradiated splenocytes pulsed with the top 62 H-2Kb synthetic peptides added at 1 μM final concentration.
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Figure 7: mLama4 and mAlg8 stimulate CD8+ T cell lines generated against d42m1-T3 following αPD-1a, CD8+ T cell lines generated from splenocytes of individual d42m1-T3 tumour bearing mice that rejected their tumours after αPD-1 therapy were incubated with irradiated d42m1-T3 tumour cells (or F244 tumour cells) treated with blocking mAb specific for H-2Kb, and/or H-2Db and IFN-γ production quantitated. Data are presented as means ± s.e.m and are representative of two independent experiments. Samples were compared using an unpaired, two-tailed Student’s t test (***p<0.001). b, IFN-γ release by the CTL 74 T cell line following co-culture with naïve irradiated splenocytes pulsed with the top 62 H-2Kb synthetic peptides added at 1 μM final concentration.

Mentions: To independently validate these observations, we established CD8+ T cell lines from spleens of mice that had rejected d42m1-T3 tumours after αPD-1 treatment. These T cells produced IFN-γ when co-cultured with d42m1-T3 but not F244 or other independent sarcoma lines. Stimulation was restricted by H-2Kb but not H-2Db (Extended Data Fig. 3a) and the only predicted epitopes that stimulated these T cell lines were mLama4 and mAlg8 (Extended Data Fig. 3b) and not their WT forms (Extended Data Fig. 4a).


Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens.

Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, Ivanova Y, Hundal J, Arthur CD, Krebber WJ, Mulder GE, Toebes M, Vesely MD, Lam SS, Korman AJ, Allison JP, Freeman GJ, Sharpe AH, Pearce EL, Schumacher TN, Aebersold R, Rammensee HG, Melief CJ, Mardis ER, Gillanders WE, Artyomov MN, Schreiber RD - Nature (2014)

mLama4 and mAlg8 stimulate CD8+ T cell lines generated against d42m1-T3 following αPD-1a, CD8+ T cell lines generated from splenocytes of individual d42m1-T3 tumour bearing mice that rejected their tumours after αPD-1 therapy were incubated with irradiated d42m1-T3 tumour cells (or F244 tumour cells) treated with blocking mAb specific for H-2Kb, and/or H-2Db and IFN-γ production quantitated. Data are presented as means ± s.e.m and are representative of two independent experiments. Samples were compared using an unpaired, two-tailed Student’s t test (***p<0.001). b, IFN-γ release by the CTL 74 T cell line following co-culture with naïve irradiated splenocytes pulsed with the top 62 H-2Kb synthetic peptides added at 1 μM final concentration.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4279952&req=5

Figure 7: mLama4 and mAlg8 stimulate CD8+ T cell lines generated against d42m1-T3 following αPD-1a, CD8+ T cell lines generated from splenocytes of individual d42m1-T3 tumour bearing mice that rejected their tumours after αPD-1 therapy were incubated with irradiated d42m1-T3 tumour cells (or F244 tumour cells) treated with blocking mAb specific for H-2Kb, and/or H-2Db and IFN-γ production quantitated. Data are presented as means ± s.e.m and are representative of two independent experiments. Samples were compared using an unpaired, two-tailed Student’s t test (***p<0.001). b, IFN-γ release by the CTL 74 T cell line following co-culture with naïve irradiated splenocytes pulsed with the top 62 H-2Kb synthetic peptides added at 1 μM final concentration.
Mentions: To independently validate these observations, we established CD8+ T cell lines from spleens of mice that had rejected d42m1-T3 tumours after αPD-1 treatment. These T cells produced IFN-γ when co-cultured with d42m1-T3 but not F244 or other independent sarcoma lines. Stimulation was restricted by H-2Kb but not H-2Db (Extended Data Fig. 3a) and the only predicted epitopes that stimulated these T cell lines were mLama4 and mAlg8 (Extended Data Fig. 3b) and not their WT forms (Extended Data Fig. 4a).

Bottom Line: Yet, clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer-induced immunosuppression.Monoclonal-antibody-based therapies targeting CTLA-4 and/or PD-1 (checkpoint blockade) have yielded significant clinical benefits-including durable responses--to patients with different malignancies.These results reveal that tumour-specific mutant antigens are not only important targets of checkpoint blockade therapy, but they can also be used to develop personalized cancer-specific vaccines and to probe the mechanistic underpinnings of different checkpoint blockade treatments.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.

ABSTRACT
The immune system influences the fate of developing cancers by not only functioning as a tumour promoter that facilitates cellular transformation, promotes tumour growth and sculpts tumour cell immunogenicity, but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion. Yet, clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer-induced immunosuppression. In many individuals, immunosuppression is mediated by cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), two immunomodulatory receptors expressed on T cells. Monoclonal-antibody-based therapies targeting CTLA-4 and/or PD-1 (checkpoint blockade) have yielded significant clinical benefits-including durable responses--to patients with different malignancies. However, little is known about the identity of the tumour antigens that function as the targets of T cells activated by checkpoint blockade immunotherapy and whether these antigens can be used to generate vaccines that are highly tumour-specific. Here we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T-cell rejection antigens following anti-PD-1 and/or anti-CTLA-4 therapy of mice bearing progressively growing sarcomas, and we show that therapeutic synthetic long-peptide vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Although mutant tumour-antigen-specific T cells are present in progressively growing tumours, they are reactivated following treatment with anti-PD-1 and/or anti-CTLA-4 and display some overlapping but mostly treatment-specific transcriptional profiles, rendering them capable of mediating tumour rejection. These results reveal that tumour-specific mutant antigens are not only important targets of checkpoint blockade therapy, but they can also be used to develop personalized cancer-specific vaccines and to probe the mechanistic underpinnings of different checkpoint blockade treatments.

Show MeSH
Related in: MedlinePlus