Journal ArticleDOI
MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma
Scott J. Rodig,Scott J. Rodig,Daniel Gusenleitner,Donald G. Jackson,Evisa Gjini,Anita Giobbie-Hurder,Chelsea Jin,Han Chang,Scott B. Lovitch,Christine Horak,Jeffrey S. Weber,Jason L. Weirather,Jedd D. Wolchok,Michael A. Postow,Michael A. Postow,Anna C. Pavlick,Jason Chesney,F. Stephen Hodi +17 more
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TLDR
It is shown that MHC class I expression in advanced melanoma predicted resistance to anti–CTLA-4, but not anti-PD-1, treatment, which may need MHCclass II to be effective, which explains why patients on combined therapy do better on average, with one drug overcoming the limitations of the other.Abstract:
Combination anti–cytotoxic T lymphocyte antigen 4 (CTLA-4) and anti–programmed cell death protein 1 (PD-1) therapy promotes antitumor immunity and provides superior benefit to patients with advanced-stage melanoma compared with either therapy alone. T cell immunity requires recognition of antigens in the context of major histocompatibility complex (MHC) class I and class II proteins by CD8+ and CD4+ T cells, respectively. We examined MHC class I and class II protein expression on tumor cells from previously untreated melanoma patients and correlated the results with transcriptional and genomic analyses and with clinical response to anti–CTLA-4, anti–PD-1, or combination therapy. Most (>50% of cells) or complete loss of melanoma MHC class I membrane expression was observed in 78 of 181 cases (43%), was associated with transcriptional repression of HLA-A, HLA-B, HLA-C, and B2M, and predicted primary resistance to anti–CTLA-4, but not anti–PD-1, therapy. Melanoma MHC class II membrane expression on >1% cells was observed in 55 of 181 cases (30%), was associated with interferon-γ (IFN-γ) and IFN-γ–mediated gene signatures, and predicted response to anti–PD-1, but not anti–CTLA-4, therapy. We conclude that primary response to anti–CTLA-4 requires robust melanoma MHC class I expression. In contrast, primary response to anti–PD-1 is associated with preexisting IFN-γ–mediated immune activation that includes tumor-specific MHC class II expression and components of innate immunity when MHC class I is compromised. The benefits of combined checkpoint blockade may be attributable, in part, to distinct requirements for melanoma-specific antigen presentation to initiate antitumor immunity.read more
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The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy
TL;DR: A better understanding of how these variables cooperate to affect tumour–host interactions is needed to optimize the implementation of precision immunotherapy.
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Cancer immunoediting and resistance to T cell-based immunotherapy
Jake S. O’Donnell,Jake S. O’Donnell,Michele W.L. Teng,Michele W.L. Teng,Mark J. Smyth,Mark J. Smyth +5 more
TL;DR: How a deeper understanding of the mechanisms underlying the cancer immunoediting process can provide insight into the development of resistance to immunotherapies and the strategies that can be used to overcome such resistance is discussed.
Journal ArticleDOI
Tumour-intrinsic resistance to immune checkpoint blockade.
Anusha Kalbasi,Antoni Ribas +1 more
TL;DR: How tumour cells can resist immune checkpoint blockade, for example, by resistance to interferon signalling and through immune-evasive oncogenic signalling pathways is described.
Journal ArticleDOI
Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I
Keisuke Yamamoto,Anthony Venida,Julian Yano,Douglas E. Biancur,Miwako Kakiuchi,Suprit Gupta,Albert S. W. Sohn,Subhadip Mukhopadhyay,Elaine Y. Lin,Seth J. Parker,Robert S. Banh,Joao A. Paulo,Kwun Wah Wen,Jayanta Debnath,Grace E. Kim,Joseph D. Mancias,Douglas T. Fearon,Douglas T. Fearon,Douglas T. Fearon,Rushika M. Perera,Alec C. Kimmelman +20 more
TL;DR: It is shown that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves theAutophagy cargo receptor NBR1 and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice.
Journal ArticleDOI
Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma
David Liu,David Liu,Bastian Schilling,Bastian Schilling,Derek Liu,Derek Liu,Antje Sucker,Elisabeth Livingstone,Livnat Jerby-Arnon,Lisa Zimmer,Ralf Gutzmer,Imke Satzger,Carmen Loquai,Stephan Grabbe,Natalie I. Vokes,Natalie I. Vokes,Claire A. Margolis,Claire A. Margolis,Jake Conway,Jake Conway,Meng Xiao He,Meng Xiao He,Haitham Elmarakeby,Haitham Elmarakeby,Felix Dietlein,Felix Dietlein,Diana Miao,Diana Miao,Adam Tracy,Helen Gogas,Simone M. Goldinger,Jochen Utikal,Jochen Utikal,Christian U. Blank,Ricarda Rauschenberg,Dagmar von Bubnoff,Angela M. Krackhardt,Angela M. Krackhardt,Benjamin Weide,Sebastian Haferkamp,Felix Kiecker,Ben Izar,Ben Izar,Levi A. Garraway,Aviv Regev,Keith T. Flaherty,Annette Paschen,Eliezer M. Van Allen,Eliezer M. Van Allen,Dirk Schadendorf +49 more
TL;DR: In this paper, the authors analyzed a clinically annotated cohort of patients with melanoma treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors.
References
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