Computerised counting of tumour infiltrating lymphocytes in 90 breast cancer specimens
Introduction
Different studies conducted over the past decades have shown that inflammation in the tumour is a common feature of many malignant neoplasms [3], [13], [21]; inflammation is associated with good prognosis [17], poor prognosis [15] or of no effect [1], [18]. In breast cancer the role of tumour infiltrating lymphocytes (TILs) remains controversial, but it is clear that the T cell response to tumour cells is complex in terms of the molecules recognised on the latter and the different types of T cells activated during the response. The mechanisms of T-cell-mediated tumour cell killing require T cytotoxic and T helper cells together with macrophages and tumour antigens. Another set of lymphocytes, the natural killer (NK) cells, seems to have tumoricidal activity that is not dependent on prior sensitisation. Other cells, the lymphokine activated killer (LAK) cells, join the mechanism of immunologic tumour cytotoxicity [9], [10], [16]. Patients receiving interleukin 2 (IL-2) treatment have been reported to show changes in proliferative responses to IL-2 [2], [19], and to induce effector cells able to directly destroy NK-resistant target cells [8], [10], [11].
Since there is no general agreement as to how different classes of TILs associate between themselves and with different histological types of carcinoma, we have used monoclonal antibodies to evaluate the presence of some of the lymphocytes implicated in immunologic cytotoxicity in 90 breast cancers. Moreover, we developed a computerised system of counting stained cells within the tumour in order to obtain comparisons and correlations between the different classes of TILs. In a subgroup of patients we also evaluated the lymphocyte status in the peripheral blood in order to compare it to that found in healthy blood donors.
Section snippets
Patient data
A consecutive series of 90 primary breast carcinomas was analysed. All patients were females between 31 and 88 years of age (mean and median age were 57). According to the TNM classification of cancer staging, 45 (50%) were classified as T1, 37 (41.1%) as T2 and 8 (8.9%) as T3. Lymph node metastasis, as determined by histological examination, was noted in 47/90 cases (52.2%), the remaining 43 patients were lymph node negative.
With regard to the tumours, 46 out of the 90 (51%) were classified as
Results
The expression of the various CDs on tumour infiltrating lymphocytes is shown in Table 1. CD3 was the most expressed antigen (64.4% of the tumours displayed CD3+TILs), while CD25 was the least expressed, present in only 11 tumours. Overall, CD8+ cells outnumbered CD4+ cells (with mean values of 77 and 53 cells/UA, respectively), and indeed the ratio CD4+/CD8+ was less than 1 in 30 out of the 50 tumours (60%) which were infiltrated by both CD4- and CD8-positive cells. As shown in Table 1, CD3+
Discussion
Infiltration by lymphoreticular cells is a common feature of many human malignant neoplasms [21], breast cancer included. This study was innovative in that immunocytochemistry was followed by computerised counting of TILs performed on a serial section; by this method we have obtained an overall view of the TILs in the tumours and found patterns of inflammation composed of different cell types individually numbered. We found that the presence of a malignant tumour did not always lead to an
Acknowledgements
We are grateful to the Regione Puglia for financial support. Grant 24/4624/111.
References (22)
- et al.
The relative significance of prognostic factors in breast carcinoma
Br. J. Cancer
(1971) - et al.
Phase I evaluation of recombinant IL-2 in patient with advanced malignant disease
J. Clin. Oncol.
(1986) - et al.
Immunohistologic characterization of major histocompatibility antigens and inflammatory cellular infiltrate in human breast cancer
J. Natl. Cancer
(1983) - et al.
Characterization of T-lymphocyte subpopulations infiltrating primary breast cancer
Cancer Immunol. Immun.
(1989) - et al.
Histological grading and prognosis in breast cancer
Br. J. Cancer
(1957) - et al.
Phenotypic analysis of tumor-infiltrating lymphocytes from human breast cancer
Anticancer Res.
(1992) - et al.
Lymphocytes infiltrating human breast cancer lack K-cell activity and show low level of NK-cell activity
Br. J. Cancer
(1981) - et al.
Phase I study of subcutaneously administered Interleukin 2 in combination with Interferon a 2A in patient with advanced cancer
J. Clin. Oncol.
(1996) - et al.
Effect of LAK cells activated by IL-2 on MCF-7 human breast cancer cell lines maintained in organotypic culture
Cancer
(1993) - et al.
In vivo induction of the lymphokine-activated killer phenomenon: Interleukin 2-dependent human non-major histocompatibility complex-restricted cytotoxicity generated in vivo during administration of human recombinant interleukin-2
Cancer Res.
(1988)
Natural killer cells activated by interleukin 2 treatment in vivo respond to interleukin 2 primarily through the p75 receptors and maintain the p55 (TAC) negative phenotype
Cancer Res.
Cited by (47)
PLAN B for immunotherapy: Promoting and leveraging anti-tumor B cell immunity
2021, Journal of Controlled ReleaseCitation Excerpt :Despite the clinical success of T cell-mediated immunotherapy, B cells and their functions should not be neglected in immuno-oncology. B cells are the second most abundant lymphocytes in many solid tumors, accounting for up to 40–50% of intratumoral lymphocytes and 25% of whole tumor cell populations [8–11]. High numbers of B cells (up to 30%) are present in tumor-draining lymph nodes [12].
Autoantibodies: Opportunities for Early Cancer Detection
2017, Trends in CancerCitation Excerpt :The immune response in cancer is likely to be initiated by alterations in the tumor that result in increased immunogenicity of self antigens [19] or loss of immune self-tolerance [20,21]. It is now irrefutable that B cells and TA autoantibodies are involved in this process, with tumor-infiltrating B lymphocytes found in up to 25% of tumors and up to 40% of tumor-infiltrating lymphocyte populations [22–24], with prognostic significance for several solid tumors [25–28]. There is also evidence that downregulation of regulatory T cells may lead to upregulation of B cell and TA autoantibody production with favorable outcomes for some cancers [29,30].
B Lymphocytes and Cancer: A Love–Hate Relationship
2016, Trends in CancerCitation Excerpt :B cells account for up to 25% of all cells in some tumors. Furthermore, 40% of TILs in some breast cancer subjects are B cells [8–10]. Consistent with a strong immunomodulatory role for these cells, 40% of high-grade serous ovarian cancers have also been shown to contain infiltrating CD20+ B cells [11].
Rise of the natural red pigment ‘prodigiosin’ as an immunomodulator in cancer
2022, Cancer Cell International