The Hallmarks Of Successful Anticancer Immunotherapy

[Marva Richardt]

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Immunotherapy is revolutionizing the clinical management of multiple tumors. However, only a fraction of patients with cancer responds to immunotherapy, and currently available immunotherapeutic agents are expensive and generally associated with considerable toxicity, calling for the identification of robust predictive biomarkers. The overall genomic configuration of malignant cells, potentially favoring the emergence of immunogenic tumor neoantigens, as well as specific mutations that compromise the ability of the immune system to recognize or eradicate the disease have been associated with differential sensitivity to immunotherapy in preclinical and clinical settings. Along similar lines, the type, density, localization, and functional orientation of the immune infiltrate have a prominent impact on anticancer immunity, as do features of the tumor microenvironment linked to the vasculature and stroma, and systemic factors including the composition of the gut microbiota. On the basis of these considerations, we outline the hallmarks of successful anticancer immunotherapy.

In the 10 years since the publication of the paper, it has become increasingly clear that both exploitation of immune mechanisms and evasion of immune surveillance are skills that cancer cells should acquire on their way to giving rise to a tumor. A comprehensive cellular, molecular, and genetic interpretation of the initially somewhat fuzzy evidence of the importance of such acquisition has also been worked out. Three such immune hallmarks are certainly required:

These three capabilities and acquisition of the genetic changes required to put them into practice are constant and essential features of natural and experimental cancers. Their strength, however, may vary from one kind of tumor to another, and even more variable are the mechanisms through which the various types of cancer undertake these activities. Acquisition of a specific genome change, therefore, is not important, whereas acquisition of these capabilities is crucial, irrespective of the mechanisms involved.

The importance of an inflammatory microenvironment is so strong that even the time frame within which an oncogene-addicted cell population gives rise to a tumor in transgenic mice is modulated by the reactive stroma that surrounds the cancer lesion [9]. Inflammation and carcinogenesis are linked even in the absence of external inflammatory stimuli. Oncogene-driven signals activate intrinsic pro-inflammatory pathways that affect the time frame within which a carcinoma appears and progresses [6, 10]. Genome-wide microarray analysis in transgenic mice identifies cytokine genes whose increased expression in the tumor microenvironment is naturally induced by the transformed cells and required for their progression [11]. The inflammatory cytokines produced can be both involved in autocrine loops directly fueling tumor cell proliferation [12] and released by immune/inflammatory cells recruited to the site of epithelial transformation [13]. Inhibition of the NF-kB pathway in these immune cells modifies stroma cell components and limits tumor expansion [14, 15].

Murine molecular data are directly endorsed by many epidemiological studies in humans that link extrinsic and intrinsic inflammatory pathways with an increased risk of cancer [16]. The increased risk of gastric cancer in the setting of bacterial infections is linked to the polymorphisms in genes coding for pro-inflammatory cytokines [17]. These findings show how extrinsic and intrinsic inflammatory pathways conspire along the road to cancer. Molecular definition of the ways in which chronic inflammation contributes to viral, chemical, and intrinsic carcinogenesis in humans is opening up novel prospects for immunoprevention.

The immune surveillance theory was put forward in the 1960s. It defined the ability to identify and destroy nascent tumors as a central asset of the immune system [18, 19], but later received an apparently deadly blow when no increase in tumor incidence was observed in athymic nude mice [20, 21]. Work in the last 10 years, however, has shown that these mice are not an appropriate model for the investigation of immune surveillance, while the employment of genetically modified mice to generate defined and stable immune defects has fully vindicated this theory. Mice with genetic alterations leading to complete T- and B-cell deficiencies are more prone to spontaneous and chemical carcinogenesis than wild-type mice [22]. Additional gene defects affecting natural immune responses increase the risk of more aggressive and precocious tumors [22]. Moreover, immune mechanisms hold occult cancer at bay for periods equivalent to the natural life span of the mouse, while temporary immunodepression allows it to progress [23].

Immune surveillance mechanisms limit cancer development, but are not completely efficient. Tumors that eventually arise are those that are poorly or not-immunogenic [24]. A critical feature that distinguishes occult neoplastic lesions from overt cancer is thus their susceptibility to immune control. The ability to evade is another hallmark of cancer.

In the last 10 years, it has become evident that a tumor becomes aware of its susceptibility to immune attack and elaborates many defenses against it. These have now been defined in both cellular and molecular terms.

The increasing instability of the genome of precancerous cells favors the emergence of clones of different immunogenicity. The poorly immunogenic ones are those that sneak through the meshes of immunosurveillance. The stealthiness of clinical tumors can be seen as one of the results of an effective immunosurveillance [24]. The loss or rarefaction of the expression of the glycoproteins of the major histocompatibility complex (MHC) on the cell membrane is one of the mechanisms by which tumor stealthiness is acquired. In addition, it may result from the subversion of cell physiology as a consequence of the overexpression of oncogene-coded proteins [26, 27], and alteration of antigenic peptide-processing machinery [28, 29].

Poor MHC glycoprotein expression and hampered antigenic peptide expression on the tumor cell surface frustrate direct recognition of tumor antigens by T cells and impede direct priming of an immune response by a tumor. Moreover, they make the effector phase of the T-cell reaction against tumor-associated antigens worthless. Blockage of these two functions is a crucial issue in tumor development since T-cell-mediated cytotoxicity is an effective mechanism of tumor inhibition.

Yet even this is not enough. Through direct release of transforming growth factor (TGF)-beta, IL-10, and indoleamine 2,3-dioxygenase (IDO), or through the activation of such secretions in myeloid-derived suppressor cells, tumor-associated macrophages and dendritic cells, a tumor converts nave T cells into adaptive regulatory T (TReg) cells. Expansion of these cells is another way by which a tumor holds back host reactivity [34].

Tumors also exploit the physiologic role of natural TReg cells to block immune reactions. These cells recognize with high affinity self-antigens and block the induction of autoimmunity. The overexpression of a few tolerated self-antigens, as happens during the expansion of tumor cells overexpressing oncogene products, leads to the activation of natural TRegs. Thus, both through the exploitation of a physiologic safeguard mechanism to control autoimmunity and the ability to convert nave T cells into a suppressor population, a growing tumor biases the immune response toward immunosuppression. The activation of adaptive and natural TReg cells is triggered by specific activation of their T-cell receptor. The TReg suppressor mechanisms thus turned on are mediated by different functions:

Exposure on the cell membrane of molecules delivering negative signals (CTLA4 and LAG3) to dendritic cells. These signals inhibit the maturation of dendritic cells, block their expression of MHC and co-stimulatory molecules (CD80 and CD86) [35], activate their ability to produce IDO that leads to the generation of the immunosuppressive mediator kynurenine, and indirectly suppress genes encoding IL-6 and TNF [36].

The same group of signals triggers the activation and maintenance of anomalous functions of tolerogenic dendritic cells and tumor-associated macrophages. In this way, a growing tumor orchestrates a web of distinct but integrated suppressive activities.

The knowledge gained in the last 10 years offers the opportunity to learn how to deploy specific countermeasures to reverse the situation in favor of the immune system and, eventually, the patient. This new information could be channeled to address what seem to be the three major hallmarks for the immune control of cancer progression:

The high efficacy of vaccines in the prevention of infection by carcinogenic viruses and other infectious agents causing cancer is currently getting an extraordinary social impact. Vaccines aimed at removing an infective risk factor are being commonly used.

Hepatocellular carcinoma accounts for more than 4% of all human cancers, and 80% of cases are associated with viral infection. Vaccination against hepatitis B virus (HBV) markedly reduced the incidence of post-hepatitis hepatocellular carcinoma [44]. Since chronic inflammation plays a significant role in the onset of liver cancer that follows HBV infection, this vaccine can be viewed as a form of primary prevention of a carcinogenic chronic inflammation.

HPV causes neoplastic disorders ranging from benign warts to malignant cervical and anogenital carcinomas [45]. The worldwide implementation of vaccination programs against HPV began only a few years ago, and their long-term efficacy in the prevention of cervical carcinoma is not yet completely assessed. Initial results are extremely favorable, and almost complete prevention of carcinogenesis is foreseen [46]. Current HPV vaccines are effective in cancer prevention but devoid of therapeutic efficacy. Vaccines able to cure cervical carcinomas are actively studied [47].

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