The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Reviews co-Section Editor Dr. Sandra Demaria.
“The PD-L1 interactome demonstrates bidirectional signaling coordinating immune suppression and cancer progression in HNSCC” by Nieto et al
J Natl Cancer Inst. (2023)
Abstract:
The programmed death receptor 1 (PD-1) and ligand (PD-L1) are validated cancer targets; however, emerging mechanisms and impact of PD-L1 intracellular signaling on cancer behavior are poorly understood. PD-L1 intracellular signaling increased clonogenicity, motility, and invasiveness in multiple head and neck squamous cell carcinoma (HNSCC) models, and PD-1 binding enhanced these effects. Protein:protein proximity labeling revealed the PD-L1 interactome, distinct for unbound and bound PD-1, which initiated cancer cell-intrinsic signaling. PD-L1 binding partners interleukin enhancer-binding factors 2 and 3 transduced their effect through STAT3. PD-L1 intracellular domain deletion (Δ260-290) disrupted signaling and reversed pro-growth properties. In humanized HNSCC in vivo models bearing T cells, PD-1 binding triggered PD-L1 signaling, and dual PD-L1 and STAT3 inhibition were required to achieve tumor control. Upon PD-1 binding, the PD-L1 extracellular and intracellular domains exert a synchronized effect to promote immune evasion by inhibiting T cell function while simultaneously enhancing cancer cell invasive properties.
Why this matters: This article describes cancer cell-intrinsic PD-L1 signaling, highlighting a new biology of this immune checkpoint ligand that needs to be further understood for its role in resistance to immunotherapy and other paradoxically negative effects of agents targeting PD1/PDL1.
“T cell egress via lymphatic vessels is tuned by antigen encounter and limits tumor control” by Steele et al
Nat Immunol. (2023)
Abstract:
Antigen-specific CD8+ T cell accumulation in tumors is a prerequisite for effective immunotherapy, and yet the mechanisms of lymphocyte transit are not well defined. Here we show that tumor-associated lymphatic vessels control T cell exit from tumors via the chemokine CXCL12, and intratumoral antigen encounter tunes CXCR4 expression by effector CD8+ T cells. Only high-affinity antigen downregulates CXCR4 and upregulates the CXCL12 decoy receptor, ACKR3, thereby reducing CXCL12 sensitivity and promoting T cell retention. A diverse repertoire of functional tumor-specific CD8+ T cells, therefore, exit the tumor, which limits the pool of CD8+ T cells available to exert tumor control. CXCR4 inhibition or loss of lymphatic-specific CXCL12 boosts T cell retention and enhances tumor control. These data indicate that strategies to limit T cell egress might be an approach to boost the quantity and quality of intratumoral T cells and thereby response to immunotherapy.
Why this matters: In this article the authors show that lymphatics play an active role in regulating T cell presence within a tumor, bringing some attention to an often neglected but critical component of the tumor microenvironment.
“B-cell-specific checkpoint molecules that regulate anti-tumour immunity” by Bod et al
Nature (2023)
Abstract:
The role of B cells in anti-tumour immunity is still debated and, accordingly,immunotherapies have focused on targeting T and natural killer cells to inhibit tumour growth1,2. Here, using high-throughput flow cytometry as well as bulk and single-cell RNA-sequencing and B-cell-receptor-sequencing analysis of B cells temporally during B16F10 melanoma growth, we identified a subset of B cells that expands specifically in the draining lymph node over time in tumour-bearing mice. The expanding B cell subset expresses the cell surface molecule T cell immunoglobulin and mucin domain 1 (TIM-1, encoded by Havcr1) and a unique transcriptional signature, including multiple co-inhibitory molecules such as PD-1, TIM-3, TIGIT and LAG-3. Although conditional deletion of these co-inhibitory molecules on B cells had little or no effect on tumour burden, selective deletion of Havcr1 in B cells both substantially inhibited tumour growth and enhanced effector T cell responses. Loss of TIM-1 enhanced the type 1 interferon response in B cells, which augmented B cell activation and increased antigen presentation and co-stimulation, resulting in increased expansion of tumour-specific effector T cells. Our results demonstrate that manipulation of TIM-1-expressing B cells enables engagement of the second arm of adaptive immunity to promote anti-tumour immunity and inhibit tumour growth.
Why this matters: Here TIM-1 is shown to be a key checkpoint receptor for B cells and an actionable target to increase tumor rejection, opening the door to new therapeutic options.
“Immune landscape in invasive ductal and lobular breast cancer reveals a divergent macrophage-driven microenvironment” by Onkar et al
Nat. Cancer (2023)
Abstract:
T cell-centric immunotherapies have shown modest clinical benefit thus far for estrogen receptor-positive (ER+) breast cancer. Despite accounting for 70% of all breast cancers, relatively little is known about the immunobiology of ER+ breast cancer in women with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC). To investigate this, we performed phenotypic, transcriptional and functional analyses for a cohort of treatment-naive IDC (n = 94) and ILC (n = 87) tumors. We show that macrophages, and not T cells, are the predominant immune cells infiltrating the tumor bed and the most transcriptionally diverse cell subset between IDC and ILC. Analysis of cellular neighborhoods revealed an interplay between macrophages and T cells associated with longer disease-free survival in IDC but not ILC. Our datasets provide a rich resource for further interrogation into immune cell dynamics in ER+IDC and ILC and highlight macrophages as a potential target for ER+ breast cancer.
Why this matters: It is know that breast cancer is a heterogeneous disease with multiple subtypes that have different immune contexture and responsiveness to immunotherapy. However, this is the first study to take a deep dive into the immune microenvironment of two types of hormone receptor-positive breast cancer: ductal and lobular cancer, showing important differences that have implication for treatment.