PD-1/PD-L1 co-inhibition shapes anticancer T cell immunodominance: facing the consequences of an immunological ménage à trois

S. M.Mansour Haeryfar, Todd Schell

Research output: Contribution to journalComment/debate

1 Citation (Scopus)

Abstract

PD-1- and PD-L1-blocking monoclonal antibodies have shown significant promise in clinical settings and rekindled the hope for successful cancer immunotherapy. We recently demonstrated that interfering with PD-1/PD-L1 signaling selectively augments CD8+ T cell (TCD8) responses to subdominant determinants (SDDs) of a model tumor antigen. This was likely due to decreased lysis of SDD-specific TCD8 by neighboring immunodominant clones co-engaging the same antigen-presenting cells (APCs). We therefore proposed that PD-1-based checkpoint inhibitors widen the range of tumor determinants that can be effectively targeted by TCD8. Subsequently and using different tumor models, Chen et al. reported, in Proceedings of the National Academy of Sciences of the United States of America, that PD-L1 protects APCs from the lytic function of immunodominant TCD8 and that PD-L1 blockade narrows, rather than broadens, the overall anticancer T cell response. Here, we briefly compare and contrast the experimental systems employed by the two groups, which may account, at least partially, for the opposing conclusions drawn. We argue that the pathway(s) of tumor antigen presentation, direct presentation versus cross-presentation, and the intensity of PD-1 expression by immunodominant and subdominant TCD8 must be taken into consideration in rational design of anti-PD-1/PD-L1-adjuvanted tumor vaccines and therapies.

Original languageEnglish (US)
Pages (from-to)1669-1672
Number of pages4
JournalCancer Immunology, Immunotherapy
Volume67
Issue number11
DOIs
StatePublished - Nov 1 2018

Fingerprint

Neoplasm Antigens
Antigen-Presenting Cells
T-Lymphocytes
Leukocyte L1 Antigen Complex
Cross-Priming
Active Immunotherapy
Neoplasms
Cancer Vaccines
Blocking Antibodies
Antigen Presentation
Immunotherapy
Clone Cells
Monoclonal Antibodies

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

Cite this

@article{709e39890cc44b45a6bae95e08ea8785,
title = "PD-1/PD-L1 co-inhibition shapes anticancer T cell immunodominance: facing the consequences of an immunological m{\'e}nage {\`a} trois",
abstract = "PD-1- and PD-L1-blocking monoclonal antibodies have shown significant promise in clinical settings and rekindled the hope for successful cancer immunotherapy. We recently demonstrated that interfering with PD-1/PD-L1 signaling selectively augments CD8+ T cell (TCD8) responses to subdominant determinants (SDDs) of a model tumor antigen. This was likely due to decreased lysis of SDD-specific TCD8 by neighboring immunodominant clones co-engaging the same antigen-presenting cells (APCs). We therefore proposed that PD-1-based checkpoint inhibitors widen the range of tumor determinants that can be effectively targeted by TCD8. Subsequently and using different tumor models, Chen et al. reported, in Proceedings of the National Academy of Sciences of the United States of America, that PD-L1 protects APCs from the lytic function of immunodominant TCD8 and that PD-L1 blockade narrows, rather than broadens, the overall anticancer T cell response. Here, we briefly compare and contrast the experimental systems employed by the two groups, which may account, at least partially, for the opposing conclusions drawn. We argue that the pathway(s) of tumor antigen presentation, direct presentation versus cross-presentation, and the intensity of PD-1 expression by immunodominant and subdominant TCD8 must be taken into consideration in rational design of anti-PD-1/PD-L1-adjuvanted tumor vaccines and therapies.",
author = "Haeryfar, {S. M.Mansour} and Todd Schell",
year = "2018",
month = "11",
day = "1",
doi = "10.1007/s00262-018-2231-z",
language = "English (US)",
volume = "67",
pages = "1669--1672",
journal = "Cancer Immunology and Immunotherapy",
issn = "0340-7004",
publisher = "Springer Science and Business Media Deutschland GmbH",
number = "11",

}

PD-1/PD-L1 co-inhibition shapes anticancer T cell immunodominance : facing the consequences of an immunological ménage à trois. / Haeryfar, S. M.Mansour; Schell, Todd.

In: Cancer Immunology, Immunotherapy, Vol. 67, No. 11, 01.11.2018, p. 1669-1672.

Research output: Contribution to journalComment/debate

TY - JOUR

T1 - PD-1/PD-L1 co-inhibition shapes anticancer T cell immunodominance

T2 - facing the consequences of an immunological ménage à trois

AU - Haeryfar, S. M.Mansour

AU - Schell, Todd

PY - 2018/11/1

Y1 - 2018/11/1

N2 - PD-1- and PD-L1-blocking monoclonal antibodies have shown significant promise in clinical settings and rekindled the hope for successful cancer immunotherapy. We recently demonstrated that interfering with PD-1/PD-L1 signaling selectively augments CD8+ T cell (TCD8) responses to subdominant determinants (SDDs) of a model tumor antigen. This was likely due to decreased lysis of SDD-specific TCD8 by neighboring immunodominant clones co-engaging the same antigen-presenting cells (APCs). We therefore proposed that PD-1-based checkpoint inhibitors widen the range of tumor determinants that can be effectively targeted by TCD8. Subsequently and using different tumor models, Chen et al. reported, in Proceedings of the National Academy of Sciences of the United States of America, that PD-L1 protects APCs from the lytic function of immunodominant TCD8 and that PD-L1 blockade narrows, rather than broadens, the overall anticancer T cell response. Here, we briefly compare and contrast the experimental systems employed by the two groups, which may account, at least partially, for the opposing conclusions drawn. We argue that the pathway(s) of tumor antigen presentation, direct presentation versus cross-presentation, and the intensity of PD-1 expression by immunodominant and subdominant TCD8 must be taken into consideration in rational design of anti-PD-1/PD-L1-adjuvanted tumor vaccines and therapies.

AB - PD-1- and PD-L1-blocking monoclonal antibodies have shown significant promise in clinical settings and rekindled the hope for successful cancer immunotherapy. We recently demonstrated that interfering with PD-1/PD-L1 signaling selectively augments CD8+ T cell (TCD8) responses to subdominant determinants (SDDs) of a model tumor antigen. This was likely due to decreased lysis of SDD-specific TCD8 by neighboring immunodominant clones co-engaging the same antigen-presenting cells (APCs). We therefore proposed that PD-1-based checkpoint inhibitors widen the range of tumor determinants that can be effectively targeted by TCD8. Subsequently and using different tumor models, Chen et al. reported, in Proceedings of the National Academy of Sciences of the United States of America, that PD-L1 protects APCs from the lytic function of immunodominant TCD8 and that PD-L1 blockade narrows, rather than broadens, the overall anticancer T cell response. Here, we briefly compare and contrast the experimental systems employed by the two groups, which may account, at least partially, for the opposing conclusions drawn. We argue that the pathway(s) of tumor antigen presentation, direct presentation versus cross-presentation, and the intensity of PD-1 expression by immunodominant and subdominant TCD8 must be taken into consideration in rational design of anti-PD-1/PD-L1-adjuvanted tumor vaccines and therapies.

UR - http://www.scopus.com/inward/record.url?scp=85052143729&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052143729&partnerID=8YFLogxK

U2 - 10.1007/s00262-018-2231-z

DO - 10.1007/s00262-018-2231-z

M3 - Comment/debate

C2 - 30132082

AN - SCOPUS:85052143729

VL - 67

SP - 1669

EP - 1672

JO - Cancer Immunology and Immunotherapy

JF - Cancer Immunology and Immunotherapy

SN - 0340-7004

IS - 11

ER -