Regulatory T-Cells as an Emerging Barrier to Immune Checkpoint Inhibition in Lung Cancer

Principe, Daniel R.; Chiec, Lauren; Mohindra, Nisha; Munshi, Hidayatullah G.

doi:10.3389/fonc.2021.684098

Cited by 60 publications

(51 citation statements)

References 100 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In particular, the APOBEC mutational signature was identified as a potential predictive marker for immunotherapy response in some cancers [44,45]. However, an increased number of Tregs in a tumor may lead to resistance to immune checkpoint inhibitors [46,47]. Thus, our finding suggests that a combined strategy targeting Tregs in addition to immune checkpoint inhibitors would be most beneficial for a better outcome in APOBEC hypermutated breast cancer tumors.…”

Section: Resultsmentioning

confidence: 92%

Influence network model uncovers relations between biological processes and mutational signatures

Amgalan

Wójtowicz

Kim

et al. 2021

Preprint

View full text Add to dashboard Cite

There is a growing appreciation that mutagenic processes can be studied through the lenses of mutational signatures – characteristic mutation patterns attributed to individual mutagens. However, the link between mutagens and observed mutation patterns is not always obvious. While some mutation signatures have been connected to specific causes such as UV light exposure, smoking, or other biochemical processes, elucidating the causes of many signatures, especially those associated with endogenous processes, remains challenging. In addition, endogenous mutational processes interact with each other, as well as with other cellular processes, in ways that are not fully understood.To gain insights into the relations between mutational signatures and cellular processes, we developed a network-based approach termed GeneSigNet. The main idea behind the approach is to utilize gene expression and signature activities for the construction of a directed network containing two types of nodes corresponding to genes and signatures respectively. The construction utilizes a sparse partial correlation technique complemented with a higher moment-based approach assigning edge directionality when possible.Application of the GeneSigNet approach to breast and lung cancer data sets allowed us to capture a multitude of important relations between mutation signatures and cellular processes. In particular, the model suggests a causative influence of the homologous recombination deficiency signature (SBS3) on a clustered APOBEC mutation signature and linked SBS8 with the NER pathway. Interestingly, our model also uncovered a relation between APOBEC hypermutation and activation of regulatory T Cells (Tregs) known to be relevant for immunotherapy, and a relation between the APOBEC enzyme activity (SBS2) and DNA conformation changes. GeneSigNet is freely available at https://github.com/ncbi/GeneSigNet.

show abstract

Section: Resultsmentioning

confidence: 92%

Influence network model uncovers relations between biological processes and mutational signatures

Amgalan

Wójtowicz

Kim

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Indeed, increasing evidences sustain the role of new additional inhibitory immune checkpoint molecules, such as TIM-3, LAG-3, and TIGIT, in order to overcome the resistance to ICI (141,144,148). More importantly, the presence of an immune suppressive TME, mainly composed by Treg, MDSC and M2-TAM, in which cytotoxic cells reinvigorated by ICI act, is still a limitation for their anti-tumor activity, thus being acknowledged as another mechanism of resistance to ICI (32,33,37,42,43). Nonetheless, the identification of TILs with antigen specificity in the TME indicates that tumor recognition may occur and may lead to tumor growth control in the presence of an appropriate immune context (22).…”

Section: Discussionmentioning

confidence: 99%

“…Treg, myeloid derived suppressor cells (MDSC), and tumor associated macrophages (TAM)-M2 through a cytokine network contribute to the inhibition of the immune responses thus inducing immune suppression (Figure 1). Treg cells inhibit T cell responses in different ways, and, in general, are associated with poor clinical outcomes in lung cancer patients (32). Recently, an increase in PD-1+Treg has been detected in patients non-responsive to anti-PD-1/PD-L1 ICI in a study evaluating patients with NSCLC (n=27) and other solid cancers.…”

Section: Immunosuppressionmentioning

confidence: 99%

Therapeutic Implications of Tumor Microenvironment in Lung Cancer: Focus on Immune Checkpoint Blockade

et al. 2022

View full text Add to dashboard Cite

In the last decade, the treatment of non-small cell lung cancer (NSCLC) has been revolutionized by the introduction of immune checkpoint inhibitors (ICI) directed against programmed death protein 1 (PD-1) and its ligand (PD-L1), or cytotoxic T lymphocyte antigen 4 (CTLA-4). In spite of these improvements, some patients do not achieve any benefit from ICI, and inevitably develop resistance to therapy over time. Tumor microenvironment (TME) might influence response to immunotherapy due to its prominent role in the multiple interactions between neoplastic cells and the immune system. Studies investigating lung cancer from the perspective of TME pointed out a complex scenario where tumor angiogenesis, soluble factors, immune suppressive/regulatory elements and cells composing TME itself participate to tumor growth. In this review, we point out the current state of knowledge involving the relationship between tumor cells and the components of TME in NSCLC as well as their interactions with immunotherapy providing an update on novel predictors of benefit from currently employed ICI or new therapeutic targets of investigational agents. In first place, increasing evidence suggests that TME might represent a promising biomarker of sensitivity to ICI, based on the presence of immune-modulating cells, such as Treg, myeloid derived suppressor cells, and tumor associated macrophages, which are known to induce an immunosuppressive environment, poorly responsive to ICI. Consequently, multiple clinical studies have been designed to influence TME towards a pro-immunogenic state and subsequently improve the activity of ICI. Currently, the mostly employed approach relies on the association of “classic” ICI targeting PD-1/PD-L1 and novel agents directed on molecules, such as LAG-3 and TIM-3. To date, some trials have already shown promising results, while a multitude of prospective studies are ongoing, and their results might significantly influence the future approach to cancer immunotherapy.

show abstract

“…Though our study did not explore the role that LAIR2 may have in checkpoint blockade immunotherapies, several studies have highlighted a predictive role for tumor-infiltrating T reg cells in response to PD-1/PD-L1 blockade. The presence of PD-1 + or PD-L1 + T reg cells was predictive of response to checkpoint inhibitors, indicating a dependency on this pathway, to which blockade increased CD8 + T cell responses [ 49 , 50 , 51 ]. Given this observation, it is likely that LAIR2 have an adverse role in immunity induced by checkpoint inhibition.…”

Section: Discussionmentioning

confidence: 99%

Tumor-Associated Regulatory T Cell Expression of LAIR2 Is Prognostic in Lung Adenocarcinoma

Navab

et al. 2021

Cancers

View full text Add to dashboard Cite

Cancer development requires a permissive microenvironment that is shaped by interactions between tumor cells, stroma, and the surrounding matrix. As collagen receptors, the leukocyte-associated immunoglobulin-like receptor (LAIR) family allows the immune system to interact with the extracellular matrix. However, little is known about their role in regulating tumor immunity and cancer progression. Methods: Genetic analysis of resected human lung adenocarcinoma was correlated to clinical-pathological characteristics, gene ontologies, and single cell RNA sequencing (scRNASeq). LAIR2 production was determined in subsets of immune cells isolated from blood leukocytes and lung adenocarcinoma tumor. Functional assays were used to determine the role of LAIR2 in tumorigenesis. Results: LAIR2 expression was adversely prognostic in lung adenocarcinoma. LAIR2 was preferentially produced by activated CD4+ T cells and enhanced in vitro tumor invasion into collagen. scRNASeq analysis of tumor infiltrating T cells revealed that LAIR2 expression co-localized with FOXP3 expressing cells and shared a transcriptional signature with tumor-associated regulatory T (Treg) cells. A CD4+LAIR2+ Treg gene signature was prognostically significant in the TCGA dataset (n = 439; hazard ratio (HR) = 1.37; 95% confidence interval (CI), 1.05–1.77, p = 0.018) and validated in NCI Director’s Challenge lung adenocarcinoma dataset (n = 488; HR = 1.54; 95% CI, 1.14–2.09, p = 0.0045). Conclusions: Our data support a role for LAIR2 in lung adenocarcinoma tumorigenesis and identify a CD4+ LAIR2+ Treg gene signature in lung adenocarcinoma prognosis. LAIR2 provides a novel target for development of immunotherapies.

show abstract

Regulatory T-Cells as an Emerging Barrier to Immune Checkpoint Inhibition in Lung Cancer

Cited by 60 publications

References 100 publications

Influence network model uncovers relations between biological processes and mutational signatures

Influence network model uncovers relations between biological processes and mutational signatures

Therapeutic Implications of Tumor Microenvironment in Lung Cancer: Focus on Immune Checkpoint Blockade

Tumor-Associated Regulatory T Cell Expression of LAIR2 Is Prognostic in Lung Adenocarcinoma

Contact Info

Product

Resources

About