Immunotherapies such as checkpoint-blocking antibodies and adoptive cell transfer are emerging as treatments for a growing number of cancers. Despite clinical activity of immunotherapies across a range of cancer types, the majority of patients fail to respond to these treatments and resistance mechanisms remain incompletely defined. Responses to immunotherapy preferentially occur in tumors with a preexisting antitumor T-cell response that can most robustly be measured via expression of dendritic cell and CD8+ T cell-associated genes. The tumor subset with high expression of this signature has been described as the T cell-"inflamed" phenotype. Segregating tumors by expression of the inflamed signature may help predict immunotherapy responsiveness. Understanding mechanisms of resistance in both the T cell-inflamed and noninflamed subsets of tumors will be critical in overcoming treatment failure and expanding the proportion of patients responding to current immunotherapies. To maximize the impact of immunotherapy drug development, pretreatment stratification of targets associated with either the T cell-inflamed or noninflamed tumor microenvironment should be employed. Similarly, biomarkers predictive of responsiveness to specific immunomodulatory therapies should guide therapy selection in a growing landscape of treatment options. Combination strategies may ultimately require converting non-T cell-inflamed tumors into T cell-inflamed tumors as a means to sensitize tumors to therapies dependent on T-cell killing. Cancer Immunol Res; 6(9); 990-1000. ©2018 AACR.

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T Cell–Inflamed versus Non-T Cell–Inflamed Tumors: A Conceptual Framework for Cancer Immunotherapy Drug Development and Combination Therapy Selection

Publisher Summary This chapter discusses retinoids and cancer. The ability of retinoids to modify the differentiation and proliferation of both preneoplastic and neoplastic cells is one of the fundamental properties of this class of substances. Retinoic acid and other natural and synthetic retinoids inhibits two-stage phorbol ester-promoted skin carcinogenesis. Under certain conditions, retinoic acid can enhance tumor formation induced with UV irradiation. The induction of urinary bladder cancer in rodents by chemical carcinogens is a multistage process involving initiation, promotion, and propagation. As in other epithelial tissues, development of neoplasia of the urothelium is sensitive to modulation by retinoids. An inverse relationship exists between cancer risk and vitamin A consumption. β-carotene is one of several naturally occurring precursors of vitamin A. β-carotene is the primary source of retinol in most underdeveloped countries and is an important source of vitamin A. One of the most potential uses for the retinoids lies in the area of cancer prevention. The rationale for the use of retinoids in cancer prevention derives from their ability to control normal differentiation in many epithelial tissues.

Retinoids and Cancer

The literature on 506 selected chemicals has been evaluated for evidence that these chemicals induce tumors in experimental animals and this assessment comprises the Gene-Tox Carcinogen Data Base Three major sources of information were used to create this evaluated data base: all 185 chemicals determined by the International Agency for Research on Cancer to have Sufficient evidence of carcinogenic activity in experimental animals, 28 selected chemicals bioassayed for carcinogenic activity by the National Toxicology Program/National Cancer Institute and found to induce tumors in mice and rats, and 293 selected chemicals which had been evaluated in genetic toxicology and related bioassays as determined from previous Gene-Tox reports The literature data on the 239 chemicals were analyzed by the Gene-Tox Carcinogenesis Panel in an organized, rational and consistent manner Criteria were established to assess individual studies employing single chemicals and 4 categories of response were developed: Positive, Negative, Inconclusive (Equivocal) and Inconclusive After evaluating each of the individual studies on the 293 chemicals, the Panel placed each of the 506 chemicals in an overall classification category based on the strength of the evidence indicating the presence or absence of carcinogenic effects An 8-category decision scheme was established using a modified version of the International Agency for Research on Cancer approach This scheme included two categories of Positive (Sufficient and Limited), two categories of Negative (Sufficient and Limited), a category of Equivocal (the evidence of carcinogenicity from well-conducted and well-reported lifetime studies had uncertain significance and was neither clearly positive nor negative), and three categories of Inadequate (the evidence of carcinogenicity was insufficient to make a decision, however, the data suggested a positive or negative indication) Of the 506 chemicals in the Gene-Tox Carcinogen Data Base, 252 were evaluated as Sufficient Positive, 99 as Limited Positive, 40 as Sufficient Negative, 21 as Limited Negative, 1 as Equivocal, 13 as Inadequate with the data suggesting a positive indication, 32 as Inadequate with the data suggesting a negative indication, and 48 Inadequate with the data not suggesting any indication of activity This data base was analyzed and examined according to chemical class, using a 29 chemical class scheme(ABSTRACT TRUNCATED AT 400 WORDS)

Chemical carcinogens. A review and analysis of the literature of selected chemicals and the establishment of the Gene-Tox Carcinogen Data Base. A report of the U.S. Environmental Protection Agency Gene-Tox Program.

Publisher Summary This chapter discusses the aspects of the relationship between vitamin A and cancer. The lower intake of vitamin A leads to an elevated susceptibility of the animal to cancerogenic insult. The rats receiving a vitamin A-deficient diet has a higher frequency of spontaneous gastric carcinomas. The use of chemical carcinogens to produce experimental tumors with high frequency in laboratory animals shows the existence of a relationship between vitamin A and cancer. An inadequate supply of retinol (vitamin A alcohol) or its esters brings about a higher frequency of tumors. The demonstration of hyperplastic lesions of epithelial linings in vitamin A deficiency, possible alteration of vitamin A metabolism in tumor bearing patients, the effect of carcinogens on vitamin A metabolism, and occasional experiments that the dietary vitamin A level may influence the growth and incidence of experimental cancer are evident. Many tissues in vitamin A-deficient animals develop altered states of differentiation and increased rates of proliferation, which may make any carcinogen more potent.

Vitamin A and cancer.

Since initial studies identifying the important role of vitamin A and its derivatives (retinoids) in maintaining the integrity of epithelial tissues, these compounds have served as paradigms for experimental studies exploring the pharmacologic modification of carcinogenesis. Retinoids have clearly been shown to inhibit chemically induced mammary and urothelial carcinogenesis in experimental animals. Prohibitive toxicity of the parent compound, vitamin A, led to a systematic search for synthetic derivatives with an improved therapeutic index. More than 1500 such compounds have been synthesized, many retaining chemopreventive potential, but with less toxicity. Although several anecdotal reports confirming therapeutic benefits of cis-retinoic acid in patients with acute promyelocytic leukemia and myelodysplastic syndromes appeared in the late 1970s and early 1980s, the remarkable studies of Huang and his colleagues in China in 1988 reporting complete remissions in patients with this uncommon variety of acute myelogenous leukemia with the transisomer of retinoic acid (all-trans-retinoic acid) led to a resurgence of interest in the retinoids as differentiating agents for the prevention and therapy of cancer. Furthermore, molecular studies showing DNA rearrangements of the alpha nuclear receptor for retinoic acid located on chromosome 17 in patients with acute promyelocytic leukemia, a disease invariably associated with a translocation between chromosomes 15 and 17, provided a direct connection between an altered nuclear receptor and the development of a human malignancy. The retinoids also may have important beneficial effects in prevention of recurrent malignancies once the primary tumor has been treated, such as in squamous cell carcinoma of the head and neck. Because retinoids appear to be less effective in inducing differentiation in nonpromyelocytic leukemia cells, investigators have conducted a number of studies to exploit potential synergism between retinoids and other differentiating agents or biologic effectors. Differentiation therapy and chemoprevention are attractive alternative approaches to intensive cytotoxic chemotherapy. It is now clear that retinoids represent one class of compounds with which it may be possible to reverse the progression of malignant disease and prevent carcinogenesis.

Retinoids in Cancer Treatment

The chemopreventive activity of two synthetic retinamides of relatively low toxicity against N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN)-induced urinary bladder cancer was studied in F344 rats and C57BL/6 X DBA/2 F1 mice. Female and male rats were given a total dose of either 1800 or 3200 mg OH-BBN over a period of 6 or 8 weeks, respectively. Male mice were given a total dose of either 90 or 180 mg OH-BBN over a period of 9 weeks. Seven days after the final intubation of a period of 9 weeks. Seven days after the final intubation of OH-BBN, animals were fed either a placebo diet or a diet supplemented with the following retinoids: for rats, 0.8 mmol 13-cis-retinoic acid, 2 mmol N-(ethyl)-all-trans-retinamide, or 2 mmol N-(2-hydroxyethyl)-all-trans-retinamide per kg diet; and for mice, either 0.5 or 1.0 mmol of N-(ethyl)-all-trans-retinamide or N-(2-hydroxyethyl)-all-trans-retinamide per kg diet. Animals were killed 6 months after the initial gastric intubation. In comparison to male and female rats fed placebo diets, all three retinoids reduced the incidence, number, and severity of the low-grade papillary transitional cell carcinomas of the urinary bladder. Similarly, treatment of mice with either of the two retinamides reduced the incidence of highly invasive urinary bladder carcinomas. The chemopreventive effect of the less toxic retinamides was equal to or greater than that of 13-cis-retinoic acid.

E J Stanek

Papers

Inhibition of Urinary Bladder Cancer by N-(Ethyl)-all-trans-retinamide and N-(2-Hydroxyethyl)-all-trans-retinamide in Rats and Mice