With the burgeoning use of immune-based treatments for cancer, never has there been a greater need to understand the tumour microenvironment within which immune cells function and how it can be ...perturbed to inhibit tumour growth. Yet, current challenges in identifying optimal combinations of immunotherapies and engineering new cell-based therapies highlight the limitations of conventional paradigms for the study of the tumour microenvironment. Ecology has a rich history of studying predator-prey dynamics to discern factors that drive prey to extinction. Here, we describe the basic tenets of predator-prey theory as applied to 'predation' by immune cells and the 'extinction' of cancer cells. Our synthesis reveals fundamental mechanisms by which antitumour immunity might fail in sometimes counterintuitive ways and provides a fresh yet evidence-based framework to better understand and therapeutically target the immune-cancer interface.
Although immunotherapy research to date has focused largely on T cells, there is mounting evidence that tumour-infiltrating B cells and plasma cells (collectively referred to as tumour-infiltrating B ...lymphocytes (TIL-Bs)) have a crucial, synergistic role in tumour control. In many cancers, TIL-Bs have demonstrated strong predictive and prognostic significance in the context of both standard treatments and immune checkpoint blockade, offering the prospect of new therapeutic opportunities that leverage their unique immunological properties. Drawing insights from autoimmunity, we review the molecular phenotypes, architectural contexts, antigen specificities, effector mechanisms and regulatory pathways relevant to TIL-Bs in human cancer. Although the field is young, the emerging picture is that TIL-Bs promote antitumour immunity through their unique mode of antigen presentation to T cells; their role in assembling and perpetuating immunologically 'hot' tumour microenvironments involving T cells, myeloid cells and natural killer cells; and their potential to combat immune editing and tumour heterogeneity through the easing of self-tolerance mechanisms. We end by discussing the most promising approaches to enhance TIL-B responses in concert with other immune cell subsets to extend the reach, potency and durability of cancer immunotherapy.
Infiltration of breast tumors by tumor-infiltrating lymphocytes (TIL) has been associated with sensitivity to anthracycline-based chemotherapy. However, it is unclear whether this is true within the ...estrogen receptor-alpha (ER)-negative subset of breast tumors that frequently manifest high TIL levels.
The association of TIL with short-term and long-term clinical response to anthracycline-based therapy was assessed in two independent ER-negative breast cancer cohorts in which patients were categorized as TIL-high or TIL-low. We defined an eight-gene lymphocyte mRNA expression signature (including CD19, CD3D, CD48, GZMB, LCK, MS4A1, PRF1, and SELL) and used unsupervised hierarchical clustering to examine the association between TIL and short-term response to neoadjuvant chemotherapy in a previously published cohort of ER-negative tumors (n = 113). We also examined the association between TIL and long-term chemotherapeutic efficacy in a second cohort of ER-negative tumors (n = 255) with longer than 6 years of median follow-up by using tissue microarrays and immunohistochemistry (IHC) for detection of CD3, CD8, CD4, CD20, and TIA-1.
In patients with ER-negative tumors treated with neoadjuvant anthracycline-based chemotherapy, pathologic complete responses (pCRs) were achieved by 23 (74%) of 31 TIL-high patients and 25 (31%) of 80 TIL-low patients (odds ratio (OR), 6.33; 95% confidence interval (CI), 2.49 to 16.08; P < 0.0001). Multivariate logistic regression with standard clinicopathologic features demonstrated that only tumor size (P = 0.037) and TIL status (P = 0.001) were independent predictors of anthracycline response. In the second cohort, adjuvant anthracycline-based therapy was associated with increased disease-free survival (DFS) only in patients with high levels of intraepithelial CD3+ TIL (P = 0.0023). In contrast, outcomes after CMF treatment (cyclophosphamide, methotrexate, and fluorouracil) showed no association with CD3 status. In both cohorts, cytotoxic T-cells were the primary TIL subtype associated with anthracycline sensitivity. Finally, TIL significantly predicted anthracycline sensitivity for both the Her2-positive and triple-negative tumor phenotypes.
ER-negative breast cancers with high levels of TIL have heightened sensitivity to anthracycline-based chemotherapy, as assessed by the immediate response to neoadjuvant therapy and long-term outcome following adjuvant therapy. Investigations of TIL-based predictive tests to identify patients likely to benefit from anthracycline-based treatments are warranted.
Ovarian cancer remains a challenging disease for which improved treatments are urgently needed. Most patients present with advanced disease that is highly responsive to surgery combined with ...platinum- and taxane-based chemotherapy, with a state of minimal residual disease being achieved in many cases. However, chemotherapy-resistant recurrent tumors typically appear within 1-5 years and are ultimately fatal. Recently, several groups have shown that ovarian tumors are often infiltrated by activated T cells at the time of diagnosis, and patients with dense infiltrates of CD3⁺CD8⁺ T cells experience unexpectedly favorable progression-free and overall survival. Other cell types in the immune infiltrate oppose anti-tumor immunity, including CD4⁺CD25⁺FoxP3⁺ regulatory T cells, CD8⁺ regulatory T cells, macrophages, and dendritic cells. The composition of immune infiltrates is shaped by the expression of cytokines, chemokines, antigens, major histocompatibility complex molecules, and costimulatory molecules. The relationship between these various immunological factors is reviewed here with a strong emphasis on outcomes data so as to create a knowledge base that is well grounded in clinical reality. With improved understanding of the functional properties of natural CD8⁺ T-cell responses to ovarian cancer, there is great potential to improve clinical outcomes by amplifying host immunity.
The presence of CD8(+) tumor-infiltrating lymphocytes (TIL) is associated with prolonged survival in high-grade serous ovarian cancer (HGSC) and other epithelial cancers. Survival is most strongly ...associated with intraepithelial versus intrastromal CD8(+) TILs; however, the mechanisms that promote the intraepithelial localization of TILs remain poorly understood. We hypothesized that intraepithelial CD8(+) TILs, like normal mucosal intraepithelial lymphocytes, might express CD103, a subunit of αE/β7 integrin, which binds E-cadherin on epithelial cells.
A large collection of primary ovarian tumors (HGSC, endometrioid, mucinous, and clear cell) was analyzed by immunohistochemistry for the presence of TIL-expressing CD103. The activation and differentiation status of CD103(+) TILs were assessed by flow cytometry. The prognostic significance of TIL subsets was evaluated by Kaplan-Meier analysis.
CD103(+) TILs were present in all major ovarian cancer subtypes and were most abundant in HGSC. CD103(+) TILs were preferentially localized to epithelial regions of tumors and were comprised predominantly of CD8(+) T cells expressing activation (HLA-DR, Ki-67, PD-1) and cytolytic (TIA-1) markers, as well as CD56(+) NK cells. Tumor infiltration by CD103(+) TILs was strongly associated with patient survival in HGSC. Tumors containing CD8(+) TILs that were CD103(-) showed poor prognosis equivalent to tumors lacking CD8(+) TILs altogether.
CD103(+) TILs comprise intraepithelial, activated CD8(+) T cells, and NK cells and are strongly associated with patient survival in HGSC. CD103 may serve as a useful marker for enriching the most beneficial subsets of TILs for immunotherapy.
Highlights • Favorable prognosis in ovarian cancer is associated with CD8+, CD4+ and CD20+ TIL. • TIL are most common in high-grade serous cancers with BRCA1 disruption. • TIL confer a distinct ...‘immunoreactive’ gene expression profile. • The immune system somehow contends with extensive intratumoral heterogeneity.
B cells and cancer Engelhard, Victor; Conejo-Garcia, Jose R.; Ahmed, Rafi ...
Cancer cell,
10/2021, Letnik:
39, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Tumor-infiltrating B cells complement T cell-mediated antitumor immunity. A panel of experts share their views on the complexity of B cells within the tumor microenvironment, the variety of ...mechanisms by which these cells control tumor growth, their organization in tertiary lymphoid structures, and their association with immunotherapy response.
Tumor-infiltrating lymphocytes (TIL), in particular CD8(+) T cells and CD20(+) B cells, are strongly associated with survival in ovarian cancer and other carcinomas. Although CD8(+) TIL can mediate ...direct cytolytic activity against tumors, the role of CD20(+) TIL is poorly understood. Here, we investigate the possible contributions of CD20(+) TIL to humoral and cellular tumor immunity.
Tumor and serum specimens were obtained from patients with high-grade serous ovarian cancer. CD8(+) and CD20(+) TIL were analyzed by immunohistochemistry and flow cytometry. Immunoglobulin molecules were evaluated by DNA sequencing. Serum autoantibody responses to the tumor antigens p53 and NY-ESO-1 were measured by ELISA.
The vast majority of CD20(+) TIL were antigen experienced, as evidenced by class-switching, somatic hypermutation, and oligoclonality, yet they failed to express the canonical memory marker CD27. CD20(+) TIL showed no correlation with serum autoantibodies to p53 or NY-ESO-1. Instead, they colocalized with activated CD8(+) TIL and expressed markers of antigen presentation, including MHC class I, MHC class II, CD40, CD80, and CD86. The presence of both CD20(+) and CD8(+) TIL correlated with increased patient survival compared with CD8(+) TIL alone.
In high-grade serous ovarian tumors, CD20(+) TIL have an antigen-experienced but atypical CD27(-) memory B-cell phenotype. They are uncoupled from serum autoantibodies, express markers of antigen-presenting cells, and colocalize with CD8(+) T cells. We propose that the association between CD20(+) TIL and patient survival may reflect a supportive role in cytolytic immune responses.
IgA nephropathy frequently leads to progressive CKD. Although interest surrounds use of immunosuppressive agents added to standard therapy, several recent studies have questioned efficacy of these ...agents. Depleting antibody-producing B cells potentially offers a new therapy. In this open label, multicenter study conducted over 1-year follow-up, we randomized 34 adult patients with biopsy-proven IgA nephropathy and proteinuria >1 g/d, maintained on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with well controlled BP and eGFR<90 ml/min per 1.73 m
, to receive standard therapy or rituximab with standard therapy. Primary outcome measures included change in proteinuria and change in eGFR. Median baseline serum creatinine level (range) was 1.4 (0.8-2.4) mg/dl, and proteinuria was 2.1 (0.6-5.3) g/d. Treatment with rituximab depleted B cells and was well tolerated. eGFR did not change in either group. Rituximab did not alter the level of proteinuria compared with that at baseline or in the control group; three patients in each group had ≥50% reduction in level of proteinuria. Serum levels of galactose-deficient IgA1 or antibodies against galactose-deficient IgA1 did not change. In this trial, rituximab therapy did not significantly improve renal function or proteinuria assessed over 1 year. Although rituximab effectively depleted B cells, it failed to reduce serum levels of galactose-deficient IgA1 and antigalactose-deficient IgA1 antibodies. Lack of efficacy of rituximab, at least at this stage and severity of IgA nephropathy, may reflect a failure of rituximab to reduce levels of specific antibodies assigned salient pathogenetic roles in IgA nephropathy.
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