After a century of controversy, the notion that the immune system regulates cancer development is experiencing a new resurgence. An overwhelming amount of data from animal models--together with compelling data from human patients--indicate that a functional cancer immunosurveillance process indeed exists that acts as an extrinsic tumor suppressor. However, it has also become clear that the immune system can facilitate tumor progression, at least in part, by sculpting the immunogenic phenotype of tumors as they develop. The recognition that immunity plays a dual role in the complex interactions between tumors and the host prompted a refinement of the cancer immunosurveillance hypothesis into one termed "cancer immunoediting." In this review, we summarize the history of the cancer immunosurveillance controversy and discuss its resolution and evolution into the three Es of cancer immunoediting--elimination, equilibrium, and escape.

The three Es of cancer immunoediting.

The induction of optimal systemic antitumor immunity involves the priming of both CD4+ and CD8+ T cells specific for tumor-associated antigens. The role of CD4+ T helper cells (Th) in this response has been largely attributed to providing regulatory signals required for the priming of major histocompatibility complex class I restricted CD8+ cytolytic T lymphocytes, which are thought to serve as the dominant effector cell mediating tumor killing. However, analysis of the effector phase of tumor rejection induced by vaccination with irradiated tumor cells transduced to secrete granulocyte/macrophage colony-stimulating factor indicates a far broader role for CD4+ T cells in orchestrating the host response to tumor. This form of immunization leads to the simultaneous induction of Th1 and Th2 responses, both of which are required for maximal systemic antitumor immunity. Cytokines produced by these CD4+ T cells activate eosinophils as well as macrophages that produce both superoxide and nitric oxide. Both of these cell types then collaborate within the site of tumor challenge to cause its destruction.

https://rupress.org/jem/article-pdf/188/12/2357/1117684/98-1698.pdf

The Central Role of CD4+ T Cells in the Antitumor Immune Response

https://www.europeanurology.com/article/S0302-2838(13)01199-8/pdf/eau-guidelines-on-prostate-cancer-part-ii-treatment-of-advanced-relapsing-and-castration-resistant-prostate-cancer

EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer ☆

The pathophysiological significance of tumor infiltrating lymphocytes remains controversial. To clarify their role, we performed clinicopathological analysis of CD8+ T cells in 131 cases of human colorectal cancer. CD8+ T cells were classified into three groups by their localization: (a) those infiltrated within cancer cell nests; (b) those distributed in the cancer stroma; and (c) those present along the invasive margin (tumor-host interface). Of these, CD8+ T cells within cancer cell nests were most significantly associated with a better survival of patients by both mono- and multivariate analyses. The impact on survival was similar to that of Dukes' staging. Granzyme B+ cytoplasmic granules were detected in lymphocytes within cancer cell nests, confirming their activated, cytotoxic phenotype. CD8 and Ki-67 double immunohistochemistry confirmed higher proliferative activity of CD8+ T cells within cancer cell nests. Our data suggested that human colorectal cancer tissue was infiltrated by various numbers of T cells that had cytotoxic phenotype, contributing to a better survival of patients. This infiltration of colorectal cancer cell nests by CD8+ T cells could be a novel prognostic factor.

/pdf/cd8-t-cells-infiltrated-within-cancer-cell-nests-as-a-2hegt5rvqq.pdf

CD8+ T Cells Infiltrated within Cancer Cell Nests as a Prognostic Factor in Human Colorectal Cancer

BACKGROUND
Primary cutaneous melanoma is often infiltrated by lymphocytes that provide the opportunity to study what may be the local immunologic reaction to the tumor and to correlate the presence of these lymphocytes with overall survival. In an attempt to delineate the histologic diagnostic criteria, to classify different categories of lymphocytic infiltrates, previously described by Elder et al. as brisk, nonbrisk, and absent, and to verify their prognostic significance, we reviewed 285 consecutive cases of primary cutaneous melanomas (American Joint Committee on Cancer Stage I and II).

METHODS
In addition to clinical variables (age, sex, and location of tumor) and the presence of tumor infiltrating lymphocytes in the vertical growth phase, the histopathologic attributes reviewed included mitotic rate, thickness, and regression. The results were derived from independent histopathologic review by two pathologists (C.G.C., M.C.M., Jr.) on separate occasions. A multivariate analysis of survival was performed with the Cox's regression model.

RESULTS
The 5- and 10-year survival rates for melanoma with a vertical growth phase and a brisk infiltrate were 77% and 55%, respectively. For tumors with a nonbrisk infiltrate, the 5- and 10-year survival rates were 53% and 45%, respectively, and for tumors with absent tumor infiltrating lymphocytes, the 5- and 10-year survival rates were 37% and 27%, respectively. Mitotic index, thickness, and tumor infiltrating lymphocytes were statistically (univariate analysis) significant prognostic factors (P = 0.003, 0.000001, 0.0003, respectively), whereas the presence or absence of regression is not. In the univariate statistical analysis, the sex of patients and site of melanoma also were statistically significant (P = 0.00001 and 0.002 respectively), whereas age (P = 0.98) was not statistically significant. The multivariate analysis of thickness, mitotic rate, and tumor infiltrating lymphocytes showed that thickness and presence of tumor infiltrating lymphocytes were significant and independent histologic prognostic factors. With regard to the clinical factors, sex retained its independent prognostic significance. The histologic characteristics of melanoma with vertical growth phase (brisk, nonbrisk, and absent) are exemplified.

CONCLUSIONS
We demonstrated that when categories of tumor infiltrating lymphocytes are strictly defined, they indeed have very strong predictive value for primary cutaneous melanomas with a vertical growth phase. This work confirms the work of Clark et al. and fully illustrates the brisk, nonbrisk, and absent categories of infiltration. Finally, a multivariate analysis comparing thickness, mitotic rate and presence of tumor infiltrating lymphocytes showed that only thickness and presence of tumor infiltrating lymphocytes are significant and independent positive histologic prognostic factors. Cancer 1996;77:1303-10.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/%28SICI%291097-0142%2819960401%2977%3A7%3C1303%3A%3AAID-CNCR12%3E3.0.CO%3B2-5

Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma.

• Tumor-infiltrating lymphocytes from 120 samples of human cancers, including melanoma, renal cell carcinoma, breast cancer, sarcoma, and colon cancer, were examined. The percentage of lymphocytes recovered from the cancer varied widely; that of renal cell carcinoma was higher than that of breast or colon cancer (65% vs 45%), which was higher than that of melanomas or sarcomas (30% to 35%). The types of lymphocytes before and after interleukin 2 activation showed specific patterns. CD4 + helper T cells predominated in all tumors except melanomas, which had more CD8 + cytotoxic T cells. CD16 + natural killer cells were recovered in renal cell carcinoma and sarcomas. Three different cytotoxic lymphocytes were identified among interleukin 2–activated tumor-infiltrating lymphocytes: (1) CD3 + CD16 − cytotoxic T lymphocytes with cytotoxicity restricted to autologous tumor cells in melanomas, (2) CD3 − CD16 + natural killer cells with vigorous major histocompatibility complex–nonrestricted cytotoxicity in renal cell carcinoma, and (3) CD3 + CD16 − T cells with modest levels of major histocompatibility complex–nonstricted cytotoxicity in all cancers except melanomas. Thus, there was considerable diversity of tumor-infiltrating lymphocytes among these histologically distinct tumors with respect to magnitude of lymphocyte infiltration, phenotypic expression, and functional capacity. ( Arch Surg . 1990;125:200-205)

Patterns of human tumor-infiltrating lymphocytes in 120 human cancers.

Long-Term Followup of Incontinence and Obstruction After Salvage Cryosurgical Ablation of the Prostate: Results in 143 Patients

The present study evaluated the in vivo biological activity of synthetic muramyl tripeptide, CGP 19835A, when encapsulated into phosphatidylcholine liposomes (POPC-19835A) and administered as an p.o. immunomodulator to BALB/c mice. Liposomes were rapidly absorbed in the intestine and reached the systemic circulation within 4 h. Alveolar macrophages harvested from the lungs of mice 24 h after a single p.o. feeding of POPC-19835A were tumoricidal toward syngeneic murine renal cell carcinoma target cells. Repeated daily feedings with POPC-19835A generated sustained activation of the alveolar macrophages. Activation of peritoneal macrophages to the tumoricidal state required at least three daily feedings of POPC-19835A. In vitro studies demonstrated the release of tumor necrosis factor alpha and interleukin 6 by macrophages activated by POPC-19835A in the presence of gamma-interferon. Interleukin 1 and nitric oxide were not induced in macrophages by this liposomal preparation. Daily administration of POPC-19835A after i.v. injection of renal cell carcinoma tumor in BALB/c mice inhibited the development of experimental lung metastasis and confirmed the potential role of long-term therapy with this new p.o. immunomodulator.

https://cancerres.aacrjournals.org/content/canres/54/22/5882.full.pdf

Andrew C. von Eschenbach

Papers

Patterns of human tumor-infiltrating lymphocytes in 120 human cancers.

Long-Term Followup of Incontinence and Obstruction After Salvage Cryosurgical Ablation of the Prostate: Results in 143 Patients

In Vivo Modulation of Macrophage Tumoricidal Activity by Oral Administration of the Liposome-encapsulated Macrophage Activator CGP 19835A

Corrigendum: Combination adriamycin and suramin induces apoptosis in bcl-2 expressing prostate carcinoma cells (Cancer Letters (1995) 93 (147-155))