Targeting CTLA-4 in cancer: Is it the ideal companion for PD-1 blockade immunotherapy combinations?

Immunotherapy approaches boosting spontaneous and durable antitumor immune responses through immune checkpoint blockade are revolutionizing treatment and patient outcomes in solid tumors and hematological malignancies. Among the various inhibitory molecules employed by the immune system to regulate the adaptive immune responses, cytotoxic T lymphocyte antigen-4 (CTLA-4) is the first successfully targeted immune checkpoint molecule in the clinic, giving rise to significant but selective benefit either when targeted alone or in combination with anti-programmed cell death protein-1 (PD-1) antibodies (Abs). However, the use of anti-CTLA-4 Abs was associated with the incidence of autoimmune-like adverse events (AEs), which were particularly frequent and severe with the use of combinational strategies.

The rationale behind targeting the ICOS-ICOS ligand costimulatory pathway in cancer immunotherapy.

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.

Tumor infiltrating B-cells signal functional humoral immune responses in breast 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.

Targeting PD-1 in cancer: Biological insights with a focus on breast cancer.

Programmed cell death-1 (PD-1) receptor and its ligands physiologically regulate the activity of the adaptive immune system to limit excessive inflammatory processes, thus preventing normal tissue damage. Tumor cells escape from the host immune surveillance using this pathway, rendering it relevant therapeutic target. Despite the relevant clinical efficacy observed in patients with solid and hematological malignancies, the clinical benefit of these novel treatments is limited to a relatively restricted number of patients.

Age-related changes in the BACH2 and PRDM1 genes in lymphocytes from healthy donors and chronic lymphocytic leukemia patients.

Background: Age-related genetic changes in lymphocyte subsets are not currently well documented. BACH2 is a transcription factor that plays an important role in immune-mediated homeostasis by tightly regulating PRDM1 expression in both B-cells and T-cells. BACH2 gene expression is highly sensitive to DNA damage in aged mice.

FOXP1 negatively regulates tumor infiltrating lymphocyte migration in human breast cancer.

Background: FOXP1, a transcriptional regulator of lymphocyte development, is abnormally expressed in some human tumors. This study investigated FOXP1-mediated regulation of tumor infiltrating lymphocytes (TIL) in untreated primary breast cancer (BC).

Methods: FOXP1 expression was analyzed in tissues from primary untreated breast tumors, BC cell lines and the METABRIC gene expression BC dataset.

Quantifying Tertiary Lymphoid Structure-Associated Genes in Formalin-Fixed Paraffin-Embedded Breast Cancer Tissues.

Tertiary lymphoid structures (TLS) have been detected in several types of human solid tumors. These structures are thought to regulate local adaptive immune responses that can promote or antagonize tumor progression. Despite positive prognostic values associated with a TLS presence in several studies, discrepancies still exist.

The transcription factors Runx3 and ThPOK cross-regulate acquisition of cytotoxic function by human Th1 lymphocytes.

Cytotoxic CD4 (CD4) T cells are emerging as an important component of antiviral and antitumor immunity, but the molecular basis of their development remains poorly understood. In the context of human cytomegalovirus infection, a significant proportion of CD4 T cells displays cytotoxic functions. We observed that the transcriptional program of these cells was enriched in CD8 T cell lineage genes despite the absence of ThPOK downregulation.

PD-1CXCR5CD4 T Cells Play Defense in Cancer and Offense in Arthritis.

T follicular helper (TFH) cells are characteristically defined by their CXCR5 positivity and homing to B cell follicles in secondary lymphoid organs (SLO). An expanded subpopulation of functionally comparable and phenotypically similar PD-1CXCR5CD4 T cells were recently identified in breast cancer (BC) and rheumatoid arthritis (RA) to have beneficial or detrimental roles, respectively, but are they inflammatory tissue effector TFH cells?

CXCL13-producing TFH cells link immune suppression and adaptive memory in human breast cancer.

T follicular helper cells (TFH cells) are important regulators of antigen-specific B cell responses. The B cell chemoattractant CXCL13 has recently been linked with TFH cell infiltration and improved survival in human cancer. Although human TFH cells can produce CXCL13, their immune functions are currently unknown.

Tumor-infiltrating lymphocyte composition, organization and PD-1/ PD-L1 expression are linked in breast cancer.

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.

FOXP1 is a regulator of quiescence in healthy human CD4 T cells and is constitutively repressed in T cells from patients with lymphoproliferative disorders.

The forkhead box P1 (FOXP1) transcription factor has been shown to regulate the generation and maintenance of quiescent naïve murine T cells. In humans, FOXP1 expression has been correlated with overall survival in patients with peripheral T-cell lymphoma (PTCL), although its regulatory role in T-cell function is currently unknown. We found that FOXP1 is normally expressed in all human leukocyte subpopulations.

Circulating (CD3(-)CD19(+)CD20(-)IgD(-)CD27(high)CD38(high)) Plasmablasts: A Promising Cellular Biomarker for Immune Activity for Anti-PLA2R1 Related Membranous Nephropathy?

Membranous nephropathy (MN) is a kidney specific autoimmune disease mainly mediated by anti-phospholipase A2 receptor 1 autoantibody (PLA2R1 Ab). The adequate assessment of chimeric anti-CD20 monoclonal antibody, rituximab (RTX), efficacy is still needed to improve clinical outcome of patient with MN. We evaluated the modification of plasmablasts (CD3(-)CD19(+)CD20(-)IgD(-)CD27(high)CD38(high)), a useful biomarker of RTX response in other autoimmune diseases, and memory (CD3(-)CD19(+)CD20(+)IgD(-)CD27(+)CD38(-)) and naive (CD3(-)CD19(+)CD20(+)IgD(+)CD27(-)CD38(low)) B cells by fluorescence-activated cell sorter analysis in PLA2R1 related MN in one patient during the 4 years of follow-up after RTX.

A simple and rapid protocol to non-enzymatically dissociate fresh human tissues for the analysis of infiltrating lymphocytes.

The ability of malignant cells to evade the immune system, characterized by tumor escape from both innate and adaptive immune responses, is now accepted as an important hallmark of cancer. Our research on breast cancer focuses on the active role that tumor infiltrating lymphocytes play in tumor progression and patient outcome. Toward this goal, we developed a methodology for the rapid isolation of intact lymphoid cells from normal and abnormal tissues in an effort to evaluate them proximate to their native state.

Tumor-infiltrating follicular helper T cells: The new kids on the block.

By analyzing CD4 lymphocytes in human breast carcinomas, we have recently uncovered the presence of follicular helper T cells in lesions exhibiting an extensive immune infiltrate. The presence of these specialized CD4 T cells, which localize to the germinal centers of peritumoral tertiary lymphoid structures found in extensively infiltrated neoplastic lesions, predicts improved disease outcome among breast carcinoma patients.

CD4⁺ follicular helper T cell infiltration predicts breast cancer survival.

CD4⁺ T cells are critical regulators of immune responses, but their functional role in human breast cancer is relatively unknown. The goal of this study was to produce an image of CD4⁺ T cells infiltrating breast tumors using limited ex vivo manipulation to better understand the in vivo differences associated with patient prognosis. We performed comprehensive molecular profiling of infiltrating CD4⁺ T cells isolated from untreated invasive primary tumors and found that the infiltrating T cell subpopulations included follicular helper T (Tfh) cells, which have not previously been found in solid tumors, as well as Th1, Th2, and Th17 effector memory cells and Tregs.