Combined PARP and WEE1 inhibition triggers anti-tumor immune response in BRCA1/2 wildtype triple-negative breast cancer.

Novel therapeutic strategies that can effectively combine with immunotherapies are needed in the treatment of triple-negative breast cancer (TNBC). We demonstrate that combined PARP and WEE1 inhibition are synergistic in controlling tumour growth in BRCA1/2 wild-type TNBC preclinical models. The PARP inhibitor (PARPi) olaparib combined with the WEE1 inhibitor (WEE1i) adavosertib triggered increases in anti-tumour immune responses, including STING pathway activation.

Tucatinib promotes immune activation and synergizes with programmed cell death-1 and programmed cell death-ligand 1 inhibition in HER2-positive breast cancer.

Background: Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors have poor efficacy in patients with trastuzumab-resistant advanced HER2-positive breast cancer. Tucatinib is a potent, selective anti-HER2 tyrosine kinase inhibitor with proven clinical benefit in the advanced setting in patients with trastuzumab resistance. We investigated if tucatinib can alter the tumor microenvironment and if this could be harnessed for therapeutic efficacy.

Intratumoral CD8 T cells with a tissue-resident memory phenotype mediate local immunity and immune checkpoint responses in breast cancer.

CD8 tumor-infiltrating lymphocytes with a tissue-resident memory T (T) cell phenotype are associated with favorable prognosis in patients with triple-negative breast cancer (TNBC). However, the relative contribution of CD8 T cells to anti-tumor immunity and immune checkpoint blockade efficacy in breast cancer remains unknown. Here, we show that intratumoral CD8 T cells in murine mammary tumors transcriptionally resemble those from TNBC patients.

Checkpoint inhibitor immunotherapy diminishes oocyte number and quality in mice.

Loss of fertility is a major concern for female reproductive-age cancer survivors, since a common side-effect of conventional cytotoxic cancer therapies is permanent damage to the ovary. While immunotherapies are increasingly becoming a standard of care for many cancers-including in the curative setting-their impacts on ovarian function and fertility are unknown. We evaluated the effect of immune checkpoint inhibitors blocking programmed cell death protein ligand 1 and cytotoxic T lymphocyte-associated antigen 4 on the ovary using tumor-bearing and tumor-free mouse models.

Immune cellular networks underlying recovery from influenza virus infection in acute hospitalized patients.

How innate and adaptive immune responses work in concert to resolve influenza disease is yet to be fully investigated in one single study. Here, we utilize longitudinal samples from patients hospitalized with acute influenza to understand these immune responses. We report the dynamics of 18 important immune parameters, related to clinical, genetic and virological factors, in influenza patients across different severity levels.

HLA-B*27:05 alters immunodominance hierarchy of universal influenza-specific CD8+ T cells.

Seasonal influenza virus infections cause 290,000-650,000 deaths annually and severe morbidity in 3-5 million people. CD8+ T-cell responses towards virus-derived peptide/human leukocyte antigen (HLA) complexes provide the broadest cross-reactive immunity against human influenza viruses. Several universally-conserved CD8+ T-cell specificities that elicit prominent responses against human influenza A viruses (IAVs) have been identified.

Tissue-resident memory T cells in breast cancer control and immunotherapy responses.

The presence of tumour-infiltrating lymphocytes (TILs) is associated with favourable outcomes in patients with breast cancer as well as in those with other solid tumours. T cells make up a considerable proportion of TILs and current evidence suggests that CD8 T cells are a crucial determinant of favourable clinical outcomes. Studies involving tumour material from numerous solid tumour types, including breast cancer, demonstrate that the CD8 TILs include a subpopulation of tissue-resident memory T (T) cells.

Human Mucosal-Associated Invariant T Cells in Older Individuals Display Expanded TCRαβ Clonotypes with Potent Antimicrobial Responses.

Mucosal-associated invariant T (MAIT) cells are important for immune responses against microbial infections. Although known to undergo marked numerical changes with age in humans, our understanding of how MAIT cells are altered during different phases across the human life span is largely unknown. Although also abundant in the tissues, our study focuses on MAIT cell analyses in blood.

Human γδ T-cell receptor repertoire is shaped by influenza viruses, age and tissue compartmentalisation.

Background: Although γδ T cells comprise up to 10% of human peripheral blood T cells, questions remain regarding their role in disease states and T-cell receptor (TCR) clonal expansions. We dissected anti-viral functions of human γδ T cells towards influenza viruses and defined influenza-reactive γδ TCRs in the context of γδ-TCRs across the human lifespan.

Methods: We performed Cr-killing assay and single-cell time-lapse live video microscopy to define mechanisms underlying γδ T-cell-mediated killing of influenza-infected targets.

Divergent SATB1 expression across human life span and tissue compartments.

Special AT-rich binding protein-1 (SATB1) is a global chromatin organizer capable of activating or repressing gene transcription in mice and humans. The role of SATB1 is pivotal for T-cell development, with SATB1-knockout mice being neonatally lethal, although the exact mechanism is unknown. Moreover, SATB1 is dysregulated in T-cell lymphoma and proposed to suppress transcription of the Pdcd1 gene, encoding the immune checkpoint programmed cell death protein 1 (PD-1).

Human CD8 T cell cross-reactivity across influenza A, B and C viruses.

Influenza A, B and C viruses (IAV, IBV and ICV, respectively) circulate globally and infect humans, with IAV and IBV causing the most severe disease. CD8 T cells confer cross-protection against IAV strains, however the responses of CD8 T cells to IBV and ICV are understudied. We investigated the breadth of CD8 T cell cross-recognition and provide evidence of CD8 T cell cross-reactivity across IAV, IBV and ICV.

Broad CD8 T cell cross-recognition of distinct influenza A strains in humans.

Newly-emerged and vaccine-mismatched influenza A viruses (IAVs) result in a rapid global spread of the virus due to minimal antibody-mediated immunity. In that case, established CD8 T-cells can reduce disease severity. However, as mutations occur sporadically within immunogenic IAV-derived T-cell peptides, understanding of T-cell receptor (TCRαβ) cross-reactivity towards IAV variants is needed for a vaccine design.

MAIT cells contribute to protection against lethal influenza infection in vivo.

Mucosal associated invariant T (MAIT) cells are evolutionarily-conserved, innate-like lymphocytes which are abundant in human lungs and can contribute to protection against pulmonary bacterial infection. MAIT cells are also activated during human viral infections, yet it remains unknown whether MAIT cells play a significant protective or even detrimental role during viral infections in vivo. Using murine experimental challenge with two strains of influenza A virus, we show that MAIT cells accumulate and are activated early in infection, with upregulation of CD25, CD69 and Granzyme B, peaking at 5 days post-infection.

Single-Cell Approach to Influenza-Specific CD8 T Cell Receptor Repertoires Across Different Age Groups, Tissues, and Following Influenza Virus Infection.

CD8 T cells recognizing antigenic peptides derived from conserved internal viral proteins confer broad protection against distinct influenza viruses. As memory CD8 T cells change throughout the human lifetime and across tissue compartments, we investigated how T cell receptor (TCR) composition and diversity relate to memory CD8 T cells across anatomical sites and immunological phases of human life. We used peptide-HLA tetramer magnetic enrichment, single-cell multiplex RT-PCR for both the TCR-alpha (TCRα) and TCR-beta (TCRβ) chains, and new TCRdist and grouping of lymphocyte interactions by paratope hotspots (GLIPH) algorithms to compare TCRs directed against the most prominent human influenza epitope, HLA-A*02:01-M1 (A2M1).

Clonally diverse CD38HLA-DRCD8 T cells persist during fatal H7N9 disease.

Severe influenza A virus (IAV) infection is associated with immune dysfunction. Here, we show circulating CD8 T-cell profiles from patients hospitalized with avian H7N9, seasonal IAV, and influenza vaccinees. Patient survival reflects an early, transient prevalence of highly activated CD38HLA-DRPD-1 CD8 T cells, whereas the prolonged persistence of this set is found in ultimately fatal cases.

Circulating T cells, serological memory, and tissue compartmentalization shape human influenza-specific B cell immunity.

Immunization with the inactivated influenza vaccine (IIV) remains the most effective strategy to combat seasonal influenza infections. IIV activates B cells and T follicular helper (T) cells and thus engenders antibody-secreting cells and serum antibody titers. However, the cellular events preceding generation of protective immunity in humans are inadequately understood.

Innate and adaptive T cells in influenza disease.

Influenza is a major global health problem, causing infections of the respiratory tract, often leading to acute pneumonia, life-threatening complications and even deaths. Over the last seven decades, vaccination strategies have been utilized to protect people from complications of influenza, especially groups at high risk of severe disease. While current vaccination regimens elicit strain-specific antibody responses, they fail to generate cross-protection against seasonal, pandemic and avian viruses.

Influenza-specific lung-resident memory T cells are proliferative and polyfunctional and maintain diverse TCR profiles.

The human lung harbors a large population of resident memory T cells (Trm cells). These cells are perfectly positioned to mediate rapid protection against respiratory pathogens such as influenza virus, a highly contagious respiratory pathogen that continues to be a major public health burden. Animal models show that influenza-specific lung CD8+ Trm cells are indispensable for crossprotection against pulmonary infection with different influenza virus strains.

Perturbed CD8 T cell immunity across universal influenza epitopes in the elderly.

Influenza epidemics lead to severe illness, life-threatening complications, and deaths, especially in the elderly. As CD8 T cells are associated with rapid recovery from influenza, we investigated the effects of aging on antigen-specific CD8 T cells across the universal influenza epitopes in humans. We show that aging is characterized by altered frequencies in T cell subsets, with naive T cells being partially replaced by activated effector/memory populations.

The role of CD27 in anti-viral T-cell immunity.

CD27 is a co-stimulatory immune-checkpoint receptor, constitutively expressed on a broad range of T-cells (αβ and γδ), NK-cells and B-cells. Ligation of CD27 with CD70 results in potent co-stimulatory effects. In mice, co-stimulation of CD8 T-cells through CD27 promotes immune activation and enhances primary, secondary, memory and recall responses towards viral infections.

Human mucosal-associated invariant T cells contribute to antiviral influenza immunity via IL-18-dependent activation.

Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes known to elicit potent immunity to a broad range of bacteria, mainly via the rapid production of inflammatory cytokines. Whether MAIT cells contribute to antiviral immunity is less clear. Here we asked whether MAIT cells produce cytokines/chemokines during severe human influenza virus infection.