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Keywords:

  • cytotoxic T lymphocyte;
  • idiopathic regression;
  • renal cell carcinoma;
  • T lymphocyte

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. References

Abstract  The unexplained regression of a metastasis of renal cell carcinoma (RCC) is rare phenomenon. While an immune mechanism has been proposed for spontaneous or unexplained regression of RCC, only limited data are available regarding immunological response. We report a case of a 62-year-old man with RCC whose paravertebral pleural tumor regressed after the withdrawal of interferon-α. In the present case, we demonstrate the enhancement of T cell proliferative response against autologous RCC cells secondary to the unexplained regression using the mixed-lymphocyte tumor culture. To our knowledge, the enhancement of an antitumor immunity secondary to an unexplained regression of RCC has not previously been reported.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. References

Here we report the unexplained regression of metastasis in a renal cell carcinoma (RCC) patient and an analysis of T cell proliferative activity against autologous RCC cells.

Case report

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. References

A 62-year-old man diagnosed with clear cell-type RCC of stage I (T1aNoMo, according to UICC classification1) when he underwent left nephrectomy for a 4 cm mass in September 1997. With informed consent, an autologous RCC cell line was successfully established from nephrectomy specimens. Because computed tomography (CT) 7 months after nephrectomy revealed two small nodules in the left lung, combination therapy of interferon-α (INF-α) and uracil plus tegafur (UFT) was initiated. However, CT at 4 months after the start of treatment revealed the development of a right upper paravertebral pleural tumor (Fig. 1a) and a right supradiaphragmatic pleural tumor. The patient was doing well until early November, when a cough and sputum expectoration developed. A chest X-ray revealed mild left pleural effusion. One month later, the patient became asymptomatic without additional treatment. The pleural effusion also diminished spontaneously. In January 1999, INF-α was discontinued because of retinal bleeding. The patient received only oral UFT at the same dose with no additional agents for RCC; however, CT scans 3 months after the withdrawal of INF-α revealed a resolution of the paravertebral pleural tumor (Fig. 1b). At this time, there was no significant change in the size and number of other the lesions, including the supradiaphragmatic pleural tumor. In October 2000, the patient underwent thoracotomy for two slow-growing nodules in the right lung and a supradiaphragmatic pleural tumor. The pathological examination revealed clear cell-type RCC in both the lung and supradiaphragmatic pleural tumors. The patient continued to be disease-free without further treatment for RCC until the development of a solitary lung metastasis 20 months after thoracotomy. In September 2002, he underwent thoracotomy for solitary right lung metastasis again. At present, the patient is doing well without any new lesions.

image

Figure 1. Chest computed tomography before and after unexplained regression. (a) A right upper paravertebral pleural tumor (indicated by arrow) newly developed after the start of interferon-α (INF-α) and uracil plus tegafur. (b) Computed tomography at 3 months after withdrawal of INF-α revealed the resolution of the paravertebral pleural tumor.

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Results of immunological studies

Peripheral blood mononuclear cells (PBMC) were stored frozen before, just after and 3 months after the regression of the paravertebral pleural tumor and were used for assay after thawing. We have previously reported that cancer-specific cytotoxic T lymphocytes (CTL) could be efficiently generated in vitro by coculturing PBMC with primary cultured cancer cells irradiated with 50 Gy using a medium containing interleukin-1 (167 U/mL), -2 (67 U/mL), -4 (67 U/mL) and -6 (134 U/mL).2 This technique allows lymphocyte proliferation with CTL activity against autologous RCC cells.2 In the present case, however, the culture method failed to induce lymphocyte proliferation (Fig. 2a). In contrast, when 10 ng/mL of interferon-γ (INF-γ) was added to the culture medium, marked lymphocyte proliferation in response to the addition of autologous RCC cells was observed from PBMC collected 3 months after regression. Phenotype analysis of the proliferated lymphocytes revealed a CD8-dominant T cell population (61% CD8+ and 34% CD4+).

image

Figure 2. Lymphocyte proliferation responding to autologous renal cell carcinoma (RCC) cells. Peripheral blood mononuclear cells (PBMC) were cultured with irradiated autologous RCC cells at an effector/target ratio of 10 : 1. Culture medium was supplemented with interleukin-1, -2, -4 and -6. Three weeks later, irradiated RCC cells were added again to lymphocyte culture. The number of lymphocytes was determined 1 week after addition of autologous RCC cells (indicated by arrow). (a) Lymphocyte proliferation was not observed without interferon-γ (INF-γ). (b) When 10 ng/mL of INF-γ was added to the culture medium, the lymphocytes from PBMC collected 3 months after regression of metastasis showed marked proliferation in response to addition of autologous RCC cells.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. References

We have presented a case of a patient whose paravertebral pleural lesion regressed after the withdrawal of INF-α. Although a histological examination of the lesion was not performed, an ipsilateral supradiaphragmatic pleural tumor, which developed at the same time as the paravertebral pleural lesion, had proven to be RCC metastasis by surgical specimen. The observation strongly suggests that the regressed paravertebral pleural lesion was a RCC metastasis. The patient in the present case received oral UFT for 12 months before the regression of pleural metastasis. However, the regression cannot be explained by the antitumor effect of UFT, since the lesion developed after the initiation of UFT. Although the causal role is not clear, transient pleural effusion and the withdrawal of INF-α preceded the unexplained regression. Interestingly, Kallmeyer and Dittrich also reported a case of an RCC patient whose pleural metastasis regressed after the development of pleural effusion.3

While an immune mechanism has been proposed for spontaneous or unexplained regression of RCC, only limited data are available regarding immunological response associated with this intriguing phenomenon.4 In the present case, we demonstrated the enhancement of T cell proliferative response against autologous RCC cells secondary to the unexplained regression using the mixed-lymphocyte tumor culture. The T cell proliferative response was revealed only when INF-γ was added to the CTL induction culture medium. Although the role of INF-γ is not clear, we previously reported that the INF-γ induced the CTL with high killing actitivity against autologous minced tissues of glioblastoma multiforme.5

Thus, it is possible that INF-γ may have induced stronger expression of MHC-class I molecules on the surface of tumor cells, but we cannot draw any conclusion on this point. To our knowledge, the enhancement of an antitumor immunity secondary to unexplained regression of RCC has not previously been reported.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. References