Search

Background: Programmed death (ligand) 1 (PD-(L)1) blockade and OX40/4-1BB costimulation have been separately evaluated in the clinic to elicit potent antitumor T cell responses. The precise mechanisms underlying single agent activity are incompletely understood. It also remains unclear if combining individual therapies leads to synergism, elicits novel immune mechanisms, or invokes additive effects., Methods: We performed high-dimensional flow cytometry and single-cell RNA sequencing-based immunoprofiling of murine tumor-infiltrating lymphocytes (TILs) isolated from hosts bearing B16 or MC38 syngeneic tumors. This baseline infiltrate was compared to TILs after treatment with either anti-PD-(L)1, anti-OX40, or anti-4-1BB as single agents or as double and triple combinatorial therapies. Fingolimod treatment and CXCR3 blockade were used to evaluate the contribution of intratumoral versus peripheral CD8 + T cells to therapeutic efficacy., Results: We identified CD8 + T cell subtypes with distinct functional and migratory signatures highly predictive of tumor rejection upon treatment with single agent versus combination therapies. Rather than reinvigorating terminally exhausted CD8 + T cells, OX40/4-1BB agonism expanded a stem-like PD-1 lo KLRG-1 + Ki-67 + CD8 + T cell subpopulation, which PD-(L)1 blockade alone did not. However, PD-(L)1 blockade synergized with OX40/4-1BB costimulation by dramatically enhancing stem-like TIL presence via a CXCR3-dependent mechanism., Conclusions: Our findings provide new mechanistic insights into the interplay between components of combinatorial immunotherapy, where agonism of select costimulatory pathways seeds a pool of stem-like CD8 + T cells more responsive to immune checkpoint blockade (ICB)., Competing Interests: Competing interests: Authors are present and former Pfizer employees and may hold stock/stock options in the company. Pfizer plans to file a patent application related to this work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Circulating memory CD8 T cell trafficking and protective capacity during liver-stage malaria infection remains undefined. We find that effector memory CD8 T cells (Tem) infiltrate the liver within 6 hours after malarial or bacterial infections and mediate pathogen clearance. Tem recruitment coincides with rapid transcriptional upregulation of inflammatory genes in Plasmodium-infected livers. Recruitment requires CD8 T cell-intrinsic LFA-1 expression and the presence of liver phagocytes. Rapid Tem liver infiltration is distinct from recruitment to other non-lymphoid tissues in that it occurs both in the absence of liver tissue resident memory "sensing-and-alarm" function and ∼42 hours earlier than in lung infection by influenza virus. These data demonstrate relevance for Tem in protection against malaria and provide generalizable mechanistic insights germane to control of liver infections., Competing Interests: Declarations of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

A paradigm shift in the understanding of the exhausted CD8 + T cell (T ex ) lineage is underway. Originally thought to be a uniform population that progressively loses effector function in response to persistent antigen, single-cell analysis has now revealed that CD8 + T ex is composed of multiple interconnected subpopulations. The heterogeneity within the CD8 + T ex lineage is comprised of immune checkpoint blockade (ICB) permissive and refractory subsets termed stem-like and terminally differentiated cells, respectively. These populations occupy distinct peripheral and intratumoral niches and are characterized by transcriptional processes that govern transitions between cell states. This review presents key findings in the field to construct an updated view of the spatial, transcriptional, and functional heterogeneity of anti-tumoral CD8 + T ex . These emerging insights broadly call for (re-)focusing cancer immunotherapies to center on the driver mechanism(s) underlying the CD8 + T ex developmental continuum aimed at stabilizing functional subsets., Competing Interests: All authors are employees of Pfizer, Inc. and hold stock/stock options in the company., (Copyright © 2021 Dolina, Van Braeckel-Budimir, Thomas and Salek-Ardakani.)

Protective lung tissue-resident memory CD8 + T cells (Trm) form after influenza A virus (IAV) infection. We show that IAV infection of mice generates CD69 + CD103 + and other memory CD8 + T cell populations in lung-draining mediastinal lymph nodes (mLNs) from circulating naive or memory CD8 + T cells. Repeated antigen exposure, mimicking seasonal IAV infections, generates quaternary memory (4M) CD8 + T cells that protect mLN from viral infection better than 1M CD8 + T cells. Better protection by 4M CD8 + T cells associates with enhanced granzyme A/B expression and stable maintenance of mLN CD69 + CD103 + 4M CD8 + T cells, vs the steady decline of CD69 + CD103 + 1M CD8 + T cells, paralleling the durability of protective CD69 + CD103 + 4M vs 1M in the lung after IAV infection. Coordinated upregulation in canonical Trm-associated genes occurs in circulating 4M vs 1M populations without the enrichment of canonical downregulated Trm genes. Thus, repeated antigen exposure arms circulating memory CD8 + T cells with enhanced capacity to form long-lived populations of Trm that enhance control of viral infections of the mLN., Competing Interests: SA, NV, SM, Sv, QS, RV, RS, SH, IJ, SV, NB, HX, VB, JH No competing interests declared, (© 2021, Anthony et al.)

Lung-resident primary memory CD8 + T cell populations (T rm ) induced by a single influenza infection decline within months, rendering the host susceptible to new heterosubtypic influenza infections. Here, we demonstrate that, relative to single virus exposure, repeated antigen exposure dramatically alters the dynamics of influenza-specific lung T rm populations. Lung T rm derived from repeatedly stimulated circulating memory CD8 + T cells exhibit extended durability and protective heterosubtypic immunity relative to primary lung T rm . Parabiosis studies reveal that the enhanced durability of lung T rm after multiple antigen encounters resulted from the generation of long-lasting circulating effector memory (T em ) populations, which maintained the ability to be recruited to the lung parenchyma and converted to T rm , in combination with enhanced survival of these cells in the lung. Thus, generating a long-lasting T rm precursor pool through repeated intranasal immunizations might be a promising strategy to establish long-lasting lung T rm -mediated heterosubtypic immunity against influenza., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

In the light of new findings that lung tissue resident memory CD8 + T cells (T rm ) represent major mediators of heterosubtypic immunity against influenza virus, it is of utmost importance to understand the basic biological mechanisms behind induction, formation and maintenance of this cell population. Addressing these important knowledge gaps will potentially inform development of superior, broadly protective influenza vaccines and new immunization strategies.