With the recent success of checkpoint inhibitors and other immune-modulating agents, there has been renewed interest in the combination of such agents with radiation. The biological premise behind such a strategy is that the tumor-antigen release achieved by localized radiation will promote specific tumor-targeting by the adaptive immune system, which can be augmented further by systemic immune-stimulating agents. In this manner, clinicians hope to induce a phenomenon known as the abscopal effect, whereby localized radiation results in immune-mediated tumor regression in disease sites well outside of the radiation field. In this Crossroads in Cancer Immunology article, we will present a comprehensive overview of the early clinical and pre-clinical evidence behind this approach.

Cervical cancer is the second-most-common cancer responsible for cancer-related death in women around the world. The incidence is increasing, with 450,000 new cases diagnosed worldwide and 12,340 diagnosed in the United States annually (1, 2). It is the third leading cause of death from cancer in women 15 to 34 years of age and the fifth leading cause of death in women 35 to 54 years of age, representing about 2% of all cancers in women in the United States. The disease is frequently found in women who have had multiple sex partners, smoking habits, and immune system dysfunctions (3). Cervical cancer is closely linked with human papillomavirus (HPV) infection, and HPVs are detected in 90% of cervical cancer lesions (4-6). While the E6 protein of HPV inactivates p53 and E7 inactivates the retinoblastoma (Rb) tumor suppressor protein, detailed studies on a large number of tumors indicate that viral infection alone is not sufficient for tumor development. Studies have also shown that 20 to 30 million Americans are infected with HPV (7). However, only those in a subset develop cervical cancer. Recently, HPVs have been implicated in the development of head and neck, lung, and breast cancers (8-10).Cystatins are inhibitors of cysteine proteases and are classified into a large superfamily subdivided into three families based on their location, size, and complexity of polypeptide chains (11-13). Cystatin E/M belongs to the type 2 cystatin family (cystatin C, D, E/M, F, S, SA, and SN), whose members are mainly secreted, and most of them are found abundantly in body fluids and tissues. Cystatin E/M is present as an unglycosylated 14-kDa form containing 149 amino acids and a 17-kDa form that is glycosylated. Loss of this protein seems to play a significant role in abnormal skin development (14). A null mutation of the mouse cystatin E/M gene is also correlated with development of the ichq phenotype, characterized by neonatal lethality, abnormal cornification, and desquamation. Cystatin E/M was initially identified as a downregulated transcript in metastatic breast cancers (15,16). A number of studies have implicated cystatin E/M as a human tumor suppressor gene that is inactivated in the cancers of the breast, cervix, prostate, brain, and stomach (17-23). Our studies have also shown that the inactivation of the gene is associated with homozygous deletion, promoter hypermethylation, and somatic mutations in primary tumor samples (19). Cystatin E/M gene is expressed in ductal carcinoma in situ (DCIS) but not in metastatic breast cancer, pointing to inactivation during tumor progression (16)(17)(18)24). Finally, inactivation of cystatin E/M gene is associated with the loss of expression of estrogen and progesterone receptors and HER4, indicating an association with these proteins in the development of invasive breast cancers (25). However, the molecular mechanism of cystatin E/M-mediated tumor cell growth inhibition is not yet understood.Cathepsins include a broad range of proteases, the serine (A

Purpose Stereotactic body radiotherapy (SBRT) can produce excellent local control of several types of solid tumor; however, toxicity to nearby critical structures is a concern. We found previously that in SBRT for lung cancer, the chest wall (CW) volume receiving 20, 30, or 40 Gy (V20, V30, or V40) was linked with the development of neuropathy. Here we sought to determine whether the dosimetric advantages of protons could produce lower CW doses than traditional photon-based SBRT. Methods We searched an institutional database to identify patients treated with photon SBRT for lung cancer with tumors within <2.5 cm of the CW. We found 260 cases; of these chronic grade ≥2 CW pain was identified in 23 patients. We then selected 10 representative patients from this group and generated proton SBRT treatment plans, using the identical dose of 50 Gy in 4 fractions, and assessed potential differences in CW dose between the two plans. Results The proton SBRT plans reduced the CW doses at all dose levels measured. The median CW V was 364.0 cm320 for photons and 160.0 cm3 for protons (P<0.0001); V30 was 144.6 cm3 for photons vs. 77.0 cm3 for protons (P=0.0012); V was 93.9 cm335 for photons vs. 57.9 cm3 for protons (P=0.005); V40 was 66.5 cm3 for photons vs. 45.4 cm3 for protons (P=0.0112); and mean lung dose was 5.9 Gy for photons vs. 3.8 Gy for protons (P=0.0001). Coverage of the planning target volume was comparable between the two sets of plans (96.4% for photons and 97% for protons). Conclusions From a dosimetric standpoint, proton SBRT can achieve the same coverage of the PTV while significantly reducing the dose to the CW and lung relative to photon SBRT and therefore may be beneficial for the treatment of lesions close to critical structures.

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