Inducible T cell costimulator (ICOS, cluster of differentiation (CD278)) is an activating costimulatory immune checkpoint expressed on activated T cells. Its ligand, ICOSL is expressed on ...antigen-presenting cells and somatic cells, including tumour cells in the tumour microenvironment. ICOS and ICOSL expression is linked to the release of soluble factors (cytokines), induced by activation of the immune response. ICOS and ICOSL binding generates various activities among the diversity of T cell subpopulations, including T cell activation and effector functions and when sustained also suppressive activities mediated by regulatory T cells. This dual role in both antitumour and protumour activities makes targeting the ICOS/ICOSL pathway attractive for enhancement of antitumour immune responses. This review summarises the biological background and rationale for targeting ICOS/ICOSL in cancer together with an overview of the principal ongoing clinical trials that are testing it in combination with anti-cytotoxic T lymphocyte antigen-4 and anti-programmed cell death-1 or anti-programmed cell death ligand-1 based immune checkpoint blockade.
The programmed cell death 1 (PD-1) pathway is an important regulator of immune responses in peripheral tissues, including abnormal situations such as the tumor microenvironment. This pathway is ...currently the principal target for immunotherapeutic compounds designed to block immune checkpoint pathways, with these drugs improving clinical outcomes in a number of solid and hematological tumors. Medical oncology is experiencing an immune revolution that has scientists and clinicians looking at alternative, non-redundant inhibitory pathways also involved in regulating immune responses in cancer. A variety of targets have emerged for combinatorial approaches in immune checkpoint blockade. The main purpose of this narrative review is to summarize the biological role of lymphocyte activation gene 3 (LAG3), an emerging targetable inhibitory immune checkpoint molecule. We briefly discuss its role in infection, autoimmune disease and cancer, with a more detailed analysis of current data on LAG3 expression in breast cancer. Current clinical trials testing soluble LAG3 immunoglobulin and LAG3 antagonists are also presented in this work.
Targeting inhibitory immune checkpoint molecules has dramatically changed treatment paradigms in medical oncology. Understanding the best strategies to unleash a pre-existing immune response or to ...induce an efficient immune response against tumors has emerged as a research priority. In this work, we focus on a novel target for cancer immunotherapy, the inhibitory receptor T-cell immunoglobulin and mucin domain 3 (TIM3). This narrative review describes TIM3 biology in different (tumor-infiltrating) immune cells, particularly in the immunosuppressive regulatory T cells and dysfunctional/exhausted cytotoxic T lymphocytes, but also in cells that confer innate immunity - natural killer and dendritic cells. We discuss the functional role of TIM3, its expression and its clinical significance in a variety of tumors, and confront the heterogeneous results emerging from different studies, including clinical trials of immunotherapy. Finally, this work summarizes the principal early-phase clinical trials exploring TIM3 blockade and discusses some future perspectives.
The recent success of the immune checkpoint blockade in cancer immunotherapy has modified the treatment algorithms in a variety of aggressive neoplastic diseases. Nevertheless, optimal selection of ...ideal candidates to these drugs remains a challenge. The presence, location and composition of a pre-existing tumor immune infiltrate seem to impact on the benefit from these treatments. The association between the presence of baseline tumor-infiltrating lymphocytes (TIL) and patients' outcomes has been widely investigated in breast cancer, although immunotherapeutic strategies have historically been less successful with respect to other neoplastic diseases such as melanoma and kidney cancer. TIL extent varies and has different associations with outcomes in the various breast cancer subtypes. Furthermore, the presence of baseline high TIL has been associated with an increased benefit from some chemotherapeutic and targeted agents even though some conflicting results have been observed on this regard. This review aims to summarize the state of the art of TIL in breast cancer with a focus on their assessment, prevalence and clinical implications in the different subtypes.
•The role of tumor-infiltrating lymphocytes (TIL) has been widely investigated in breast cancer.•TIL extent is heterogeneous and differently associated with outcomes in the various breast cancer subtypes.•TIL extent varies in the different stages of breast cancer (early versus advanced).•TIL may be used as a new biomarker for patient's stratification in trials of immunotherapy.
Background
The relative risk (RR) of infection for patients treated with immune checkpoint inhibitors (ICIs) is unknown.
Objectives
This study evaluated the risk of infection for patients with solid ...tumors undergoing ICI therapy based on a systematic review and meta-analysis.
Patients and Methods
The Cochrane Library, EMBASE, and Pubmed databases were searched up to 1 December 2020. Randomized trials comparing any ICI alone, with chemotherapy (CT), or with other agents
versu
s
placebo, CT, or other agents were included. Three independent reviewers extracted the data. The primary outcome was the RR of all-grade (G) and G3–5 infections for patients receiving ICI-based treatments. Random or fixed-effect models were used according to statistical heterogeneity.
Results
A total of 21,451 patients from
N
= 36 studies were eligible. ICIs were associated with a similar risk of all-grade infections (RR = 1.02; 95% CI 0.84–1.24;
P
= 0.85) versus non-ICI treatments (G1–5 events: 9.6
v
ersu
s
8.3%). When the ICIs alone were compared to CT, their use was associated with 42% less risk of all-grade infections (RR = 0.58, 95% CI 0.4–0.85;
P
= 0.01). Compared to CT, the combination of ICIs and CT increased the risk of all-grade (RR = 1.37, 95% CI 1.23–1.53;
P
< 0.01) and severe infections (RR = 1.52, 95% CI 1.17–1.96;
P
< 0.01). In anti-PD-1, anti-PD-L1, anti-CTLA-4, monotherapy, and combination trials, the RR of all-grade infections was 0.72 (95% CI 0.49–1.05;
P
= 0.09), 1.18 (95% CI 0.95–1.46;
P
= 0.13), 1.74 (95% CI 1.13–2.67;
P
= 0.01), 0.97 (95% CI 0.79–1.19;
P
= 0.75) and 2.26 (95% CI 1.34–3.8;
P
< 0.01), respectively.
Conclusions
Compared to CT alone, ICIs were safer and are recommended for frail patients. Conversely, CT + ICIs or ICIs combinations increased infection risk. Further studies are required to identify high-risk patients and evaluate the need for CT dose reduction or prophylactic myeloid growth factors.
Programmed cell death-ligand 2 (PD-L2) is one of the two ligands of the programmed cell death-1 (PD-1) receptor, an inhibitory protein mainly expressed on activated immune cells that is targeted in ...the clinic, with successful and remarkable results. The PD-1/PD-Ls axis was shown to be one of the most relevant immunosuppressive pathways in the immune microenvironment, and blocking this interaction gave rise to an impressive clinical benefit in a broad variety of solid and hematological malignancies. Although PD-L2 has been historically considered a minor ligand, it binds to PD-1 with a two- to six-fold higher affinity as compared to PD-L1. PD-L2 can be expressed by immune, stromal, or tumor cells. The aims of this narrative review are to summarize PD-L2 biology in the physiological responses of the immune system and its role, expression, and clinical significance in cancer.
Tumor-infiltrating B-cells (TIL-B) in breast cancer (BC) have previously been associated with improved clinical outcomes; however, their role(s) in tumor immunity is not currently well known. This ...study confirms and extends the correlation between higher TIL-B densities and positive outcomes through an analysis of HER2-positive and triple-negative BC patients from the BIG 02-98 clinical trial (10yr mean follow-up). Fresh tissue analyses identify an increase in TIL-B density in untreated primary BC compared to normal breast tissues, which is associated with global, CD4+ and CD8+ TIL, higher tumor grades, higher proliferation and hormone receptor negativity. All B-cell differentiation stages are detectable but significant increases in memory TIL-B are consistently present. BC with higher infiltrates are specifically characterized by germinal center TIL-B, which in turn are correlated with TFH TIL and antibody-secreting TIL-B principally located in tertiary lymphoid structures. Some TIL-B also interact directly with tumor cells. Functional analyses reveal TIL-B are responsive to BCR stimulation ex vivo, express activation markers and produce cytokines and immunoglobulins despite reduced expression of the antigen-presenting molecules HLA-DR and CD40. Overall, these data support the concept that ongoing humoral immune responses are generated by TIL-B and help to generate effective anti-tumor immunity at the tumor site.
The clinical relevance of tumor-infiltrating lymphocytes (TIL) in breast cancer (BC) has been clearly established by their demonstrated correlation with long-term positive outcomes. Nevertheless, the ...relationship between protective immunity, observed in some patients, and critical features of the infiltrate remains unresolved. This study examined TIL density, composition and organization together with PD-1 and PD-L1 expression in freshly collected and paraffin-embedded tissues from 125 patients with invasive primary BC. Tumor and normal breast tissues were analyzed using both flow cytometry and immunohistochemistry. TIL density distribution is a continuum with 25% of tumors identified as TIL-negative at a TIL density equivalent to normal breast tissues. TIL-positive tumors (75%) were equally divided into TIL-intermediate and TIL-high. Tumors had higher mean frequencies of CD4
+
T cells and CD19
+
B cells and a lower mean frequency of CD8
+
T cells compare with normal tissues, increasing the CD4
+
/CD8
+
T-cell ratio. Tertiary lymphoid structures (TLS), principally located in the peri-tumoral stroma, were detected in 60% of tumors and correlated with higher TIL infiltration. PD-1 and PD-L1 expression were also associated with higher TIL densities and TLS. TIL density, TLS and PD-L1 expression were correlated with more aggressive tumor characteristics, including higher proliferation and hormone receptor negativity. Our findings reveal an important relationship between PD-1/PD-L1 expression, increased CD4
+
T and B-cell infiltration, TIL density and TLS, suggesting that evaluating not only the extent but also the nature and location of the immune infiltrate should be considered when evaluating antitumor immunity and the potential for benefit from immunotherapies.
The present commentary synthesizes the current evidence on the role of the immune response in HER2-positive breast cancer. It points out the strengths and weaknesses of the findings observed so far, ...particularly in the early setting, including the clinical significance of scoring tumor-infiltrating lymphocytes. A figure proposing research hypotheses for the implementation of immune checkpoint blockade use for patient candidates to neoadjuvant treatment is presented.
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